Gastric retentive oral dosage form with restricted drug release in the lower gastrointestinal tract

ABSTRACT

Controlled release oral dosage forms are provided for the continuous, sustained administration of a pharmacologically active agent to the upper gastrointestinal tract of a patient in whom the fed mode as been induced. The majority of the agent is delivered, on an extended release basis, to the stomach, duodenum and upper regions of the small intestine, with drug delivery in the lower gastrointestinal tract and colon substantially restricted. The dosage form comprises a matrix of a biocompatible, hydrophilic, erodible polymer with an active agent incorporated therein, wherein the polymer is one that both swells in the presence of water and gradually erodes over a time period of hours, with swelling and erosion commencing upon contact with gastric fluid, and drug release rate primarily controlled by erosion rate.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.13/153,211, filed Jun. 3, 2011, which is a divisional of U.S. patentapplication Ser. No. 10/769,574, now U.S. Pat. No. 7,976,870, which is adivisional of U.S. patent application Ser. No. 10/024,932, filed Dec.18, 2001, abandoned, which is a continuation-in-part of U.S. patentapplication Ser. No. 10/045,816, filed on Oct. 25, 2001, abandoned, thedisclosures of which are hereby incorporated by reference in theirentirety.

TECHNICAL FIELD

The present invention relates generally to the field of drug delivery.More particularly, the invention relates to controlled release, gastricretentive dosage forms for oral administration, formulated so as todeliver the majority of the incorporated drug into the stomach and uppergastrointestinal tract, with restricted drug delivery in the lowergastrointestinal tract.

BACKGROUND OF THE INVENTION

Sustained release dosage forms for oral administration, designed todeliver a pharmacologically active agent over an extended time period,are well known. In particular, dosage forms that are capable ofdelivering drug to the stomach and gastrointestinal tract in acontrolled, “sustained release” manner are described in U.S. Pat. Nos.5,007,790 to Shell, 5,582,837 to Shell and 5,972,389 to Shell et al.,all of common assignment herewith. The dosage forms described in theaforementioned patents are comprised of particles of a hydrophilic,water-swellable polymer with the drug dispersed therein. The polymericparticles in which the drug is dispersed absorb water, causing theparticles to swell, which in turn promotes their retention in thestomach and also allows the drug contained in the particles to dissolveand then diffuse out of the particles. The polymeric particles alsorelease drug as a result of physical erosion, i.e., degradation.

Release of certain types of pharmacologically active agents or fragmentsthereof into the lower gastrointestinal tract is not desirable and maybe detrimental to a number of patients. Release of antibiotics into thecolon, for example, may disrupt the delicate balance of the naturalflora and result in conditions such as pseudomembranous colitis. Mostoral dosage forms, especially controlled release dosage forms, have thepotential to deliver a significant amount of drug to the lowergastrointestinal tract and colon.

It has now been discovered that erodible, swellable dosage forms akin tothose described in the '790, '837 and '389 patents may be modified sothat drug delivery is targeted, i.e., the active agent is primarilyreleased in the stomach and upper gastrointestinal tract, while releasein the lower gastrointestinal tract and colon is minimal.

Representative active agents with which the present invention may beused are fluoroquinolone antibiotics, i.e., fluorinated analogs ofnalidixic acid. These antibiotics are active against both gram-positiveand gram-negative bacteria, and are believed to exert their therapeuticeffect by inhibiting bacterial topoisomerase II (DNA gyrase) andtopoisomerase IV, thus blocking bacterial DNA synthesis. Fluoroquinoloneantibiotics include ciprofloxacin, clinafloxacin, enoxacin,gatifloxacin, grepafloxacin, levofloxacin, lomefloxacin, moxifloxacin,norfioxacin, ofloxacin, pefloxacin, sparfloxacin, trovafloxacin, andacid addition salts thereof.

Ciprofloxacin,1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylicacid, is available commercially from the Bayer Corporation under thetrade name Cipro®. Ciprofloxacin is of particular current interest, notonly for its utility in treating opportunistic bacterial infectionsassociated with HIV (e.g., infection with mycobacterium avium complex,or “MAC”), urinary tract infections (including those caused bymulti-drug resistant bacteria such as Pseudomonas), bacterial diarrhea(caused, for example, by Shigella, Salmonella, toxigenic E. coli, orCampylohacler), tissue, hone and joint infections (e.g., caused byorganisms such as Enterobacter), but also for its utility in inhibitingBacillus anthracis, commonly known as “anthrax.” See, for example.D'iakov et al. (1994). “Comparative Evaluation of the Effectiveness ofFluoroquinolones in Experimental Anthrax Infection,” Antihiot Khimioter.39(6): 15-19; Friedlander et al. (1993), “Postexposure ProphylaxisAgainst Experimental Inhalation Anthrax,” J. Infect. Dis. 167(5):1239-1243; Kelly et al. (1992) J Infect. Dis. 166(5): 1184-1187.Ciprofloxacin is rapidly and well absorbed from the gastrointestinal(G.I.) tract, with an absolute bioavailability in the range ofapproximately 55% to 85%, typically around 70%. With the presentlyavailable immediate release dosage form, the maximum serum concentrationis attained 1-2 hours after dosing and the serum half-life isapproximately 4 hours. Ciprofloxacin and associated uses, syntheticmethods, and formulations are described in U.S. Pat. Nos. 4,670,444;4,705,789; 4,808,583; 4,844,902; 4,957,922; 5,286,754; 5,695,784; and6,136,347.

The current ciprofloxacin dosage forms are administered once everytwelve hours. Since the effect of ciprofloxacin persists longer than the4-hour half-life of the drug (Davis et al. (1996) Drugs 51:1019-1074),extension of the duration of the plasma profile should, in theory,enable once daily delivery. However, design of a once daily dosage formwith conventional sustained release dosage forms is problematic, becauseciprofloxacin is poorly absorbed in the colon (Arder et al. (1990) Br.J. Clin. Pharmacol: 30-39) and delivery of any antibiotic to a healthycolon may lead to enterocolitis (Schact et al. (1988) Infection 16:S29),as alluded to above.

There is accordingly a need in the art to provide gastric retentivedosage forms wherein drug release in the lower gastrointestinal tractand colon is restricted, and the majority of the drug dose is deliveredto the stomach and upper gastrointestinal tract. The invention is usefulnot only in conjunction with the delivery of ciprofloxacin,fluoroquinolone antibacterial agents in general, and other antibiotics,but also with a host of active agents for which restricted delivery inthe lower intestinal tract is desirable.

SUMMARY OF THE INVENTION

The present invention is directed to the aforementioned need in the art,and provides a controlled release oral dosage form for the continuous,sustained administration of a pharmacologically active agent to theupper G.I. tract of a patient in whom the fed mode as been induced. Themajority of the agent is delivered, on an extended release basis, to thestomach, duodenum and upper regions of the small intestine, with drugdelivery in the lower gastrointestinal tract and colon substantiallyrestricted. The dosage form comprises a matrix of a biocompatible,hydrophilic, erodible polymer with an active agent incorporated therein,with the active agent preferably representing at least about 60% byvolume of the dosage form, wherein the polymer is one that both swellsin the presence of water and gradually erodes over a time period ofhours, with swelling and erosion commencing upon contact with gastricfluid.

In order to deliver the majority of the drug dose to the stomach andupper G.I. tract and avoid or at least minimize delivery of the drug tothe lower intestine and colon, the drug release period should be lessthan that of the sum of the mean gastric emptying time and the transittime through the small intestine. For drugs having low aqueoussolubility, this means that the duration of erosion—which isapproximately equivalent to the drug release period with such activeagents—should be less than that of the sum of the mean gastric emptyingtime and the transit time through the small intestine. The dosage formsof the invention are particularly adapted for delivery of active agentswhose aqueous solubility decreases as pH increases, such asciprofloxacin and other fluoroquinolone antibiotics, such that anyactive agent remaining in the dosage form upon passage from the acidicregion of the stomach and upper G.I. tract into the much more basiclower G.I. tract will not be in solution, and, therefore, not availablefor absorption.

Further, in order to minimize variability in the rate of absorption,C_(max) and t_(max) from patient to patient, it is necessary to minimizethe variability in the rate of drug release from gastric retentivedosage forms. The ratio of erosion rate “ER” obtained in vitro using adisintegration test (i.e., the rate of drug release as a result ofdosage form erosion or disintegration) to the dissolution rate “DR”obtained in vitro using a dissolution test (i.e., the rate of drugrelease as a result of swelling, dissolution, and diffusion out of thematrix), can be adjusted in the present dosage forms, not only tooptimize the site of drug delivery, but also to provide a dosage formwherein the dependency of the release profile on mechanical andhydrodynamic forces is minimized, thereby, in turn, minimizingvariability in the rate of drug release. The ratio of the aforementionedER to DR values obtained in vitro should generally be in the range ofabout 1.2:1 to 5:1, preferably about 1.2:1 to 3:1, more preferably about1.3:1 to 2:1, and most preferably about 1.5:1 to 2:1. Optimization ofthe ER to DR ratio may be controlled by adjusting the size and/or shapeof the dosage form, by selecting matrix polymers having particularswelling and erosion rates, by increasing or decreasing drug loading,and by using additives such as disintegrants and solubilizers. Forexample, the rate of diffusion of dissolved active agent out of thematrix (the DR) can be slowed relative to the rate at which the activeagent is released via polymer erosion (the ER) by increasing the volumefraction of drug and selecting a polymer that will erode faster than itwill swell.

These dosage forms can minimize or even eliminate problems such as theovergrowth of detrimental intestinal flora resulting from drugs that aretoxic to normal intestinal flora, by delivering the bulk of the drugdose to the upper G.I. tract and allowing little or no drug to reach thelower G.I. tract or colon. The dosage forms can also prevent chemicaldegradation of drugs by intestinal enzymes, as alluded to above, loss ofbioavailability of a drug due to its leaving the acidic environment ofthe stomach, and chemical degradation of a drug in the neutral toalkaline environment of the gastrointestinal tract. Finally, the dosageform can extend the drug delivery period so as to allow less frequentadministration. For example, the invention enables preparation ofonce-a-day dosage forms for the administration of fluoroquinoloneantibiotics such as ciprofloxacin, which are currently administered atleast twice daily.

When used to administer drugs that are highly soluble in aqueous acid,the active agent may be contained within a vesicle that prevents a toorapid release rate in the acidic environment of the upper G.I. tract.Suitable vesicles include, but are not limited to, liposomes andnanoparticles, including nanocrystals, nanospheres and nanocapsules.

In a further embodiment of this invention, the dosage form is a bilayertablet, a trilayer tablet, or a shell-and-core tablet, with bilayer andtrilayer tablets preferred. With the bilayer tablet, one layer containsdrug and is comprised of a polymer that is primarily erodible, and asecond, swellable layer may contain the same drug, a different drug, orno drug. The function of the swelling layer is to provide sufficientparticle size throughout the entire period of drug delivery to promotegastric retention in the fed mode. With the trilayer tablet, the outerlayers contain drug and are comprised of a polymer that is primarilyerodible, while the middle layer is swellable.

The invention additionally provides a method for using these dosageforms to administer drugs on an extended basis to the stomach, duodenumand upper sections of the small intestine, while minimizing delivery tothe lower G.I. tract and colon, as well as a method for preparing thedosage forms so as achieve the aforementioned targeted delivery profilewhile minimizing patient-to-patient variability. The latter methodinvolves preparing the dosage form with a predetermined ratio ofdisintegration release ER to dissolution release DR. The ER may beevaluated using any suitable disintegration test that is predictive ofdrug release behavior in vivo, although a particularly preferred suchtest is the standard USP Disintegration Test as set forth in USP 24-NF19, Supplement 4, Section 701, published by the United StatesPharmacopeia & National Formulary in 2001, or a modification of thestandard test. The pertinent information obtained using thedisintegration test is the “disintegration time,” a term that is usedinterchangeably herein with the terms “erosion rate,” “erosion release,”“disintegration rate,” and “disintegration release,” and generallyrefers to the time for complete disintegration of the dosage form tooccur, wherein “complete disintegration” is as defined as the state inwhich less than 10%, preferably less than 5%, of the original dosageform (or the active agent-containing layer in a bilayer or trilayertablet) remains visible. If the test is stopped prior to completedisintegration, the fraction of the dosage form that has disintegratedis noted along with the time of the monitoring period (for example, theER may be reported as “40% released at 4 hours,” “80% released at 8hours,” or the like). The DR, on the other hand, is generally evaluatedusing USP Dissolution Test equipment and the standard USP DissolutionTest as set forth in USP 24-NF 19, Supplement 4, Section 711, whichcalls for immersion of a dosage in a specified solvent at 37° C. for agiven time period, using either a basket stirring element or a paddlestirring element (respectively referred to as “Apparatus 1” and“Apparatus 2” in USP 24-NF 19). At regular time intervals, a sample ofthe solvent is withdrawn and the drug concentration therein determined,e.g., by HPLC. The pertinent information obtained using the dissolutiontest is the “dissolution release,” a term that is used interchangeablyherein with the terms “dissolution rate,” “dissolution release,”“swelling rate,” and “diffusion rate,” and refers to the time forcomplete release of drug to occur, wherein “complete release” is asdefined as the state in which greater than 90%, preferably greater than95% of the drug has been released. As with the ER, if the test isstopped prior to complete release, the fraction of drug released isnoted along with the time of the monitoring period.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1 and 2 are plots showing the in vitro release characteristics ofthe four dosage forms evaluated in Example 1, evaluated using both adisintegration test and a dissolution test.

FIGS. 3 and 4 are plots showing the difference in absorption in vivobetween the four dosage forms evaluated in Example 1.

FIG. 5 is a plot showing the release curves obtained from a single layermatrix formulation, using both a disintegration test and a dissolutiontest, as described in Example 2.

FIG. 6 is a plot showing the release curves obtained from bilayer andtrilayer tablets as described in Example 2.

FIGS. 7 and 8 are plots showing the dissolution and disintegrationprofiles at pH 1 and 6.8, respectively, obtained in vitro for thegastric retentive dosage forms evaluated in Example 3.

FIG. 9 is a plot of plasma level versus time for an in vivo studycarried out with ciprofloxacin HCl dosage forms, as described in Example4.

DETAILED DESCRIPTION OF THE INVENTION I. Definitions and Overview

Before describing the present invention in detail, it is to beunderstood that this invention is not limited to specific active agents,dosage forms, dosing regimens, or the like, as such may vary. It is alsoto be understood that the terminology used herein is for the purpose ofdescribing particular embodiments only, and is not intended to belimiting.

It must be noted that as used in this specification and the appendedclaims, the singular forms “a,” “an” and “the” include plural referentsunless the context clearly dictates otherwise. Thus, for example,reference to “an active agent” or “a pharmacologically active agent”includes a single active agent as well a two or more different activeagents in combination, reference to “a polymer” includes mixtures of twoor more polymners as well as a single polymer, and the like.

In describing and claiming the present invention, the followingterminology will be used in accordance with the definitions set outbelow.

The terms “drug,” “active agent.” and “pharmacologically active agent”are used interchangeably herein to refer to any chemical compound,complex or composition that is suitable for oral administration and thathas a beneficial biological effect, preferably a therapeutic effect inthe treatment of a disease or abnormal physiological condition. Theterms also encompass pharmaceutically acceptable, pharmacologicallyactive derivatives of those active agents specifically mentioned herein,including, but not limited to, salts, esters, amides, prodrugs, activemetabolites, analogs, and the like. When the terms “active agent,”“pharmacologically active agent” and “drug” are used, then, or when aparticular active agent is specifically identified, it is to beunderstood that applicants intend to include the active agent per se aswell as pharmaceutically acceptable, pharmacologically active salts,esters, amides, prodrugs, metabolites, analogs, etc.

The term “dosage form” denotes any form of a pharmaceutical compositionthat contains an amount of active agent sufficient to achieve atherapeutic effect with a single administration. When the formulation isa tablet or capsule, the dosage form is usually one such tablet orcapsule. The frequency of administration that will provide the mosteffective results in an efficient manner without overdosing will varywith: (1) the characteristics of the particular drug, including both itspharmacological characteristics and its physical characteristics, suchas solubility; (2) the characteristics of the swellable matrix, such asits permeability; and (3) the relative amounts of the drug and polymer.Iii most cases, the dosage form will be such that effective results willbe achieved with administration no more frequently than once every eighthours, preferably no more frequently than once every twelve hours, andeven more preferably no more frequently than once every twenty-fourhours.

The terms “treating” and “treatment” as used herein refer to reductionin severity and/or frequency of symptoms, elimination of symptoms and/orunderlying cause, prevention of the occurrence of symptoms and/or theirunderlying cause, and improvement or remediation of damage. Thus, forexample, “treating” a patient involves prevention of a particulardisorder or adverse physiological event in a susceptible individual aswell as treatment of a clinically symptomatic individual by inhibitingor causing regression of a disorder or disease.

By an “effective” amount or a “therapeutically effective amount” of adrug or pharmacologically active agent is meant a nontoxic butsufficient amount of the drug or agent to provide the desired effect.

By “pharmaceutically acceptable,” such as in the recitation of a“pharmaceutically acceptable carrier,” or a “pharmaceutically acceptableacid addition salt,” is meant a material that is not biologically orotherwise undesirable, i.e., the material may be incorporated into apharmaceutical composition administered to a patient without causing anyundesirable biological effects or interacting in a deleterious mannerwith any of the other components of the composition in which it iscontained. “Pharmacologically active” (or simply “active”) as in a“pharmacologically active “derivative, refers to a derivative having thesame type of pharmacological activity as the parent compound andapproximately equivalent in degree. When the term “pharmaceuticallyacceptable” is used to refer to a derivative (e.g., a salt) of an activeagent, it is to be understood that the compound is pharmacologicallyactive as well. When the term, “pharmaceutically acceptable” is used torefer to an excipient, it implies that the excipient has met therequired standards of toxicological and manufacturing testing or that itis on the Inactive Ingredient Guide prepared by the FDA.

The term “biocompatible” is used interchangeably with the term“pharmaceutically acceptable.”

The term “soluble,” as used herein, refers to a drug having an aqueoussolubility (measured in water at 20° C.) greater than 10%, preferablygreater than 35%, by weight. The terms “slightly soluble” and “sparinglysoluble” refer to a drug having an aqueous solubility (measured at 20°C.) in the range of 2% to 10% by weight, while drugs having an aqueoussolubility in the range of 0.001% to less than 2% by weight are referredto as “substantially insoluble.”

The term “vesicle,” as used herein, refers to a small (usually 0.01 to1.0 mm), usually spherical, membrane-bound structure that may contain orbe composed of either lipoidal or aqueous material, or both. Suitablevesieles include, but are not limited to, liposomes, nanoparticles, andmicrospheres composed of amino acids. While some of these particles,especially nanoparticles and microspheres, need not be membrane-boundstructures, for the purposes of the present invention, they areencompassed by the term “vesicle.”

The term “controlled release” is intended to refer to anydrug-containing formulation in which release of the drug is notimmediate, i.e., with a “controlled release” formulation, oraladministration does not result in immediate release of the drug into anabsorption pool. The term is used interchangeably with “nonimmediaterelease” as defined in Remington: The Science and Practice of Pharmacy,Nineteenth Ed, (Easton. Pa.: Mack Publishing Company, 1995). Asdiscussed therein, immediate and nonimmediate release can be definedkinetically by reference to the following equation:

The “absorption pool” represents a solution of the drug administered ata particular absorption site, and k_(r), k_(a) and k_(e) are first-orderrate constants for (1) release of the drug from the formulation, (2)absorption, and (3) elimination, respectively. For immediate releasedosage forms, the rate constant for drug release k_(r) is far greaterthan the absorption rate constant ka. For controlled releaseformulations, the opposite is true, i.e., k_(r)<<k_(a), such that therate of release of drug from the dosage form is the rate-limiting stepin the delivery of the drug to the target area. It should be noted thatthis simplified model uses a single first order rate constant forrelease and absorption, and that the controlled release kinetics withany particular dosage form may be much for complicated. In general,however, the term “controlled release” as used herein includes anynonimmediate release formulation.

The term “sustained release” is used in its conventional sense to referto a drug formulation that provides for gradual release of a drug overan extended period of time, and that preferably, although notnecessarily, results in substantially constant blood levels of a drugover an extended time period.

The terms “hydrophilic” and “hydrophobic” are generally defined in termsof a partition coefficient P, which is the ratio of the equilibriumconcentration of a compound in an organic phase to that in an aqueousphase. A hydrophilic compound has a P value less than 1.0, typicallyless than about 0.5, where P is the partition coefficient of thecompound between octanol and water, while hydrophobic compounds willgenerally have a P greater than about 1.0, typically greater than about5.0. The polymeric carriers herein are hydrophilic, and thus compatiblewith aqueous fluids such as those present in the human body.

The term “polymer” as used herein refers to a molecule containing aplurality of covalently attached monomer units, and includes branched,dendrimeric and star polymers as well as linear polymers. The term alsoincludes both homopolymers and copolymers, e.g., random copolymers,block copolymers and graft copolymers, as well as uncrosslinked polymersand slightly to moderately to substantially crosslinked polymers.

The terms “swellable” and “bioerodible” (or simply “erodible”) are usedto refer to the polymers used in the present dosage forms, with“swellable” polymers being those that are capable of absorbing water andphysically swelling as a result, with the extent to which a polymer canswell being determined by the degree of crosslinking, and “bioerodible”or “erodible” polymers referring to polymers that slowly dissolve and/orgradually hydrolyze in an aqueous fluid, and/or that physically erodesas a result of movement within the stomach or gastrointestinal tract.

The in vivo “release rate” and in vivo “release profile” refer to thetime it takes for the orally administered dosage form, or the activeagent-containing layer of a bilayer or trilayer tablet (again,administered when the stomach is in the fed mode) to be reduced to0-10%, preferably 0-5%, of its original size, as may be observedvisually using NMR shift reagents or paramagnetic species, radio-opaquespecies or markers, or radiolabels. Unless otherwise indicated herein,all references to in vivo tests and in vivo results refer to resultsobtained upon oral administration of a dosage form with food, such thatthe stomach is in the fed mode.

The term “fed mode,” as used herein, refers to a state which istypically induced in a patient by the presence of food in the stomach,the food giving rise to two signals, one that is said to stem fromstomach distension and the other a chemical signal based on food in thestomach. It has been determined that once the fed mode has been induced,larger particles are retained in the stomach for a longer period of timethan smaller particles. Thus, the fed mode is typically induced in apatient by the presence of food in the stomach.

In the normal digestive process, the passage of matter through thestomach is delayed by a physiological condition that is variouslyreferred to as the digestive mode, the postprandial mode, or the “fedmode.” Between fed modes, the stomach is in the interdigestive or“fasting” mode. The difference between the two modes lies in the patternof gastroduodenal motor activity.

In the fasting mode, the stomach exhibits a cyclic activity called theinterdigestive migrating motor complex (“IMMC”). This activity occurs infour phases:

Phase I, which lasts 45 to 60 minutes, is the most quiescent, with thestomach experiencing few or no contractions;

Phase II, characterized by sweeping contractions occurring in anirregular intermittent pattern and gradually increasing in magnitude;

Phase III, consisting of intense bursts of peristaltic waves in both thestomach and the small bowel, lasting for about 5 to 15 minutes; and

Phase IV is a transition period of decreasing activity which lasts untilthe next cycle begins.

The total cycle time for all four phases is approximately 90 minutes.The greatest activity occurs in Phase III, when powerful peristalticwaves sweep the swallowed saliva, gastric secretions, food particles,and particulate debris, out of the stomach and into the small intestineand colon. Phase III thus serves as an intestinal housekeeper, preparingthe upper tract for the next meal and preventing bacterial overgrowth.

The fed mode is initiated by nutritive materials entering the stomachupon the ingestion of food. Initiation is accompanied by a rapid andprofound change in the motor pattern of the upper gastrointestinaltract, over a period of 30 seconds to one minute. The change is observedalmost simultaneously at all sites along the G.I. tract and occursbefore the stomach contents have reached the distal small intestine.Once the fed mode is established, the stomach generates 3-4 continuousand regular contractions per minute, similar to those of the fastingmode but with about half the amplitude. The pylorus is partially open,causing a sieving effect in which liquids and small particles flowcontinuously from the stomach into the intestine while indigestibleparticles greater in size than the pyloric opening are retropelled andretained in the stomach. This sieving effect thus causes the stomach toretain particles exceeding about 1 cm in size for approximately 4 to 6hours.

Accordingly, the present drug delivery systems are used to administer adrug to the fed stomach and upper G.I. tract while minimizing drugrelease in the lower G.I. tract and colon. The method is particularlyuseful in conjunction with the delivery of drugs that are toxic tonormal intestinal flora or are used to treat a local condition ordisorder, e.g., a stomach ulcer. The dosage forms, having an optimizedratio of erosion rate to dissolution rate and, preferably, although notnecessarily, a volume fraction of the drug of at least 60%, provide foreffective delivery of drugs to the upper G.I. tract, with delivery tothe lower G.I. tract and colon restricted and the drug delivery periodin the upper G.I. tract extended relative to the delivery periodassociated with immediate release and prior gastric retentive dosageforms. The dosage forms are particularly suited to administration ofdrugs whose aqueous solubility decreases with increasing pH, such thatthe drug is substantially more soluble in the acidic environment of thestomach than in the more basic regions of the lower G.I. tract.

The dosage forms of the invention are comprised of at least onebiocompatible, hydrophilic, erodible polymer with a drug dispersedtherein. The swelling properties of the polymer(s) are important insofaras they promote gastric retention of the dosage forms in the fedstomach. For drug delivery to the stomach and upper G.I. tract, apolymer is used that (i) swells unrestrained dimensionally viaimbibition of gastric fluid to increase the size of the particles topromote gastric retention within the stomach of a patient in whom thefed mode has been induced, (ii) gradually erodes over a time period ofhours, with the erosion commencing upon contact with the gastric fluid,and (iii) releases the drug to the stomach, duodenum and upper G.I.tract at a rate that, in general, is primarily dependent on the erosionrate. That is, with respect to the latter requirement, preferred dosageforms have an erosion rate that is slightly faster than the swellingrate, such that drug release from the dosage form is primarilycontrolled by polymer erosion than by polymer swelling.

II. Optimization Using Disintegration and Dissolution Tests

The preferred composition of a dosage form of the invention gives risenot only to the desired drug release profile in vivo, i.e., a releaseprofile wherein the majority of the drug dose is delivered to the upperG.I. tract with restricted delivery to the lower G.I. tract, but alsoeffectively minimizes patient-to-patient variability in release profile.One of the ways the invention accomplishes this is by providing a dosageform whose ER to DR is optimized such that the ratio of ER to DR is inthe range of about 1.2:1 to 5:1, preferably about 1.2:1 to 3:1, morepreferably about 1.3:1 to 2:1, and most preferably about 1.5:1 to 2:1.

The ER may be evaluated using any suitable disintegration test, althougha particularly preferred such test is the standard USP DisintegrationTest as set forth in USP 24-NF 19, Supplement 4, Section 701, publishedby the United States Pharmacopeia & National Formulary in 2001, or amodification of the standard test. As explained in the aforementionedsection of USP 24-NF 19, the USP Disintegration apparatus consists of abasket-rack assembly, a 1000-ml beaker, 142 to 148 mm in height andhaving an outside diameter of 103 to 108 mm, a thermostatic arrangementfor heating an immersion fluid between 35° C. and 39° C., and a devicefor raising and lowering the basket in the immersion fluid at a constantfrequency rate between 29 and 32 cycles pet minute through a distance of5.3 cm to 5.7 cm. The time required for the upward and downward strokesis the same, and the volume of the fluid in the vessel is such that thewire mesh of the basket remains at least 2.5 cm below the fluid surfaceon the upward stroke, and should not descend to within less than 2.5 cmof the bottom of the vessel on the downward stroke. There should be noappreciable horizontal movement of the basket rack assembly; theassembly moves solely in a vertical direction, along its axis. Thebasket-rack assembly consists of six open-ended transparent tubes, eachhaving dimensions specified in the aforementioned section of USP 24-NF19; the tubes are held in a vertical position by two plastic plates,with six holes equidistance from the center of the plate and equallyspaced from one another. Attached to the undersurface of the lower plateis a woven stainless steel wire mesh. A suitable means is provided tosuspend the basket-rack assembly from a raising and lowering device.

Accordingly, the USP Disintegration Test is conducted using theabove-described test equipment by placing the dosage form to be testedin each basket-rack assembly, immersing the assembly in a specifiedfluid at a temperature between 35° C. and 39° C. for a given timeperiod, and raising and lowering the basket in the immersion fluidthrough a distance of about 5.5 cm at a frequency of about 30 cycles perminute. The dosage forms are visually inspected at specified times forcomplete disintegration. The particularly preferred disintegration testused in conjunction with the invention is a modification of the standardUSP Disintegration Test wherein one to three tablets are tested perbasket, an extended monitoring time is used, e.g., a four-hour totwenty-four-hour time period, generally a two-hour to twenty-four hourperiod, preferably a four-to eight-hour time period, and wherein a thinplastic disk (9.5±0.15 mm in thickness, 20.7±0.15 mm in diameter) isplaced on each dosage form (noted as optional in Section 701 of USP24-NF 19).

The DR is evaluated using a dissolution test that is predictive of drugrelease behavior, with the USP Disintegration Test (as set forth in USP24-NF 19. Supplement 4, Section 711) or a modification of the standardtest. Either of two devices is used in the USP

Disintegration Test. “Apparatus 1” and “Apparatus 2.” Apparatus 1consists of a covered vessel, a motor, a metallic drive shaft, and acylindrical basket that serves a stirring element. The vessel is made ofa material that does not sorb, react, or interfere with the dosage formsto be tested, with glass and other inert, transparent materialspreferred. The vessel is partially immersed in a water bath or placed ina heating jacket, such that the temperature inside the vessel ismaintained at 37±0.5° C. during the test, with the water in the waterbath, if used, kept inconstant, smooth motion by the rotating basket. Adevice that allows for observation of the dosage form during the test ispreferred. The vessel is cylindrical, with a hemispherical bottom andone of the following dimensions: height of 160 mm to 210 mm, insidediameter of 98 mm to 106 mm, capacity of 1 liter; height of 280 mm to300 mm, inside diameter of 98 mm to 106 mm, capacity of 2 liters; andheight of 280 mm to 300 mm, inside diameter of 145 mm to 155 mm,capacity of 4 liters. The shaft is positioned so that the distancebetween the shaft axis and the vertical axis of the vessel is less than2 mm, at all points, thus ensuring smooth rotation without significantwobble. A speed-regulating device is used that allows the shaft rotationspeed to be controlled.

USP Dissolution Apparatus 2 is similar to that of Apparatus 1, exceptthat the rotating basket is replaced with a paddle formed from a bladeand a shaft, with the blade and shaft integrated so as to comprise asingle structural entity. The paddle may be metallic (composed of forexample, 303 stainless steel) or it may be comprised of some othersuitably inert, rigid material. A distance of 25±2 mm is maintainedbetween the blade and the inside bottom of the vessel, during the test.The dosage Unit is allowed to sink to the bottom of the vessel beforerotation of the blade is started. A small, loose piece of nonreactivematerial (such as not more than a few turns of a wire helix) may beattached to dosage units that would otherwise float.

The preferred dissolution apparatus used herein is the USP Apparatus 1,using standard 40-mesh rotating baskets, a basket rotation speed of 100rpm, a 1-liter vessel containing a dissolution medium specified in theindividual USP monograph for the particular active agent and type ofdosage form being tested (e.g., 900 mL deionized (DI) water forsustained release ciprofloxacin tablets) as the dissolution medium,anti-evaporation covers, and a Distek Dissolution System 2100B USP Bathor equivalent. The dissolution test is carried out by assembling theapparatus as described above and as explained in detail in Section 711of USP 24-NF 19, filling the 1-liter vessels with 900 mL deionized (DI)water as the dissolution medium, and equilibrating the DI water to37±0.5° C. Each dosage form is weighed and placed in into a dry 40-meshbasket, and then lowered into the DI water at to. Samples are removed as5.0 mL aliquots at various time points, typically although notnecessarily at 1, 2, 4, 6 and 8 hours, from a zone midway between thesurface of the DI water and the top of the rotating basket, not lessthan 1 cm from the vessel wall. Quantitation may then be performed usingany suitable technique, with reverse phase liquid chromatography and anultraviolet detection system.

To optimize the ER-to-DR ratio for a particular drug, various dosageforms can be prepared and evaluated for their ER and DR using the abovetests. That is, one or more matrix polymers are selected along with anactive agent to be administered, and different dosage forms are preparedusing different matrix polymers and/or active agents, matrix polymers ofdifferent molecular weights, matrix polymers crosslinked to differentdegrees, and/or different amounts of different components, such aslubricants, solubilizers, disintegrants, and the like. Those dosageforms that exhibit an optimized ER-to-DR ratio, i.e., in the range ofabout 1.2:1 to 5:1, preferably about 1.2:1 to 3:1, more preferably about1.3:1 to 2:1, and most preferably about 1.5:1 to 2:1.

III. Swellable, Bioerodible Polymers

The polymer used in the dosage forms of the present invention should notrelease the drug at too rapid a rate so as to result in a drug overdoseor rapid passage into and through the upper gastrointestinal tract(i.e., in less than about four hours), nor should the polymer releasedrug too slowly to achieve the desired biological effect. That is, themajority of the drug dose should be delivered in the stomach and upperG.I. tract, but drug release in the stomach and upper G.I. tract shouldstill occur over an extended time period. Polymers that permit a rate ofdrug release that achieves the requisite pharmacokinetics for a desiredduration, as determined using the USP Dissolution and DisintegrationTests, are selected for use in the dosage forms of the presentinvention.

Polymers suitable for use in the present invention are those that bothswell upon absorption of gastric fluid and gradually erode over a timeperiod of hours. Erosion initiates simultaneously with the swellingprocess, upon contact of the surface of the dosage form with gastricfluid. Erosion reflects the dissolution of the polymer beyond thepolymer gel-solution interface where the polymer has become sufficientlydilute that it can be transported away from the dosage form by diffusionor convection. This may also depend on the hydrodynamic and mechanicalforces present in the gastrointestinal tract during the digestiveprocess. While swelling and erosion occur at the same time, it ispreferred herein that drug release should be erosion-controlled, meaningthat the selected polymer should be such that complete drug releaseoccurs primarily as a result of erosion rather than swelling anddissolution. However, swelling should take place at a rate that issufficiently fast to allow the tablet to be retained in the fed stomachfor a time period in the range of about 2-12 hours, preferably in therange of about 4-9 hours. At minimum, for an erosional gastric retentivedosage form, there should be an extended period during which the dosageform maintains its size before it is diminished by erosion.

Suitable polymers for use in the present dosage forms may be linear,branched, dendrimeric, or star polymers, and include synthetichydrophilic polymers as well as semi-synthetic and naturally occurringhydrophilic polymers. The polymers may be homopolymers or copolymers, ifcopolymers, either random copolymers, block copolymers or graftcopolymers. Synthetic hydrophilic polymers useful herein include, butare not limited to:

polyalkylene oxides, particularly poly(ethylene oxide), polyethyleneglycol and poly(ethylene oxide)-poly(propylene oxide) copolymers;

cellulosic polymers;

acrylic acid and methacrylic acid polymers, copolymers and estersthereof, preferably formed from acrylic acid, methacrylic acid, methylacrylate, ethyl acrylate, methyl methacrylate, ethyl methacrylate, andcopolymers thereof with each other or with additional acrylate speciessuch as aminoethyl acrylate;

maleic anhydride copolymers;

polymaleic acid;

poly(acrylamides) such as polyacrylamide per se, poly(methacrylamide),poly(dimethylacrylamide), and poly(N-isopropyl-acrylamide);

poly(olefinic alcohol)s such as poly(vinyl alcohol);

poly(N-vinyl lactams) such as poly(vinyl pyrrolidone), poly(N-vinylcaprolactam), and copolymers thereof;

polyols such as glycerol, polyglycerol˜articularly highly branchedpolyglycerol), propylene glycol and trimethylene glycol substituted withone or more polyalkylene oxides, e.g., mono-, di- andtri-polyoxyethylated glycerol, mono- and di-polyoxyethylated propyleneglycol, and mono- and di-polyoxyethylated trimethylene

polyoxyethylated sorbitol and polyoxyethylated glucose;

polyoxazolines, including poly(methyloxazoline) andpoly(ethyloxazoline);

polyvinylamines:

polyvinylacetates, including polyvinylacetate per seas well asethylene-vinyl acetate copolymers, polyvinyl acetate phthalate, and thelike;

polyimines, such as polyethyleneimine;

starch and starch-based polymers;

polyurethane hydrogels;

chitosan;

polysaccharide gums;

zein; and

shellac, ammoniated shellac, shellac-acetyl alcohol, and shellac n-butylstearate.

The term “cellulosic polymer” is used herein to denote a linear polymerof anhydroglucose. Cellulosic polymers that can be used advantageouslyin the present dosage forms include, without limitation,hydroxymethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose,hydroxypropyl methylcellulose, methylcellulose, ethylcellulose,cellulose acetate, cellulose acetate phthalate, cellulose acetatetrimellitate, hydroxypropyl methylcellulose phthalate,hydroxypropylcellulose phthalate, cellulose hexahydrophthalate,cellulose acetate hexahydrophthalate, carboxymethylcellulose,carboxymethylcellulose sodium, and microcrystalline cellulose. Preferredcellulosic polymers are alkyl-substituted cellulosic polymers thatultimately dissolve in the GI tract in a predictably delayed manner.Preferred alkylsubstituted cellulose derivatives are those substitutedwith alkyl groups of 1 to 3 carbon atoms each. Examples aremethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose,hydroxypropylcellulose, hydroxypropyl methylcellulose, andcarboxymethylcellulose. In terms of their viscosities, one class ofpreferred alkyl-substituted celluloses includes those whose viscosity iswithin the range of about 50 to about 110,000 centipoise as a 2% aqueoussolution at 20° C. Another class includes those whose viscosity iswithin the range of about 800 to about 6,000 centipoise as a 1% aqueoussolution at 20° C. Particularly preferred alkyl-substituted cellulosesare hydroxyethylcellulose and hydroxypropylmethylcellulose. A presentlypreferred hydroxyethylcellulose is NATRASOL® 250HX NF (NationalFormulary), available from Aqualon Company, Wilmington, Del., USA.

Polyalkylene oxides are the preferred polymers herein, and thepolyalkylene oxides that are of greatest utility are those having theproperties described above for alkyl substituted cellulose polymers. Aparticularly preferred polyalkylene oxide is poly(ethylene oxide), whichterm is used herein to denote a linear polymer of unsubstituted ethyleneoxide. Poly(ethylene oxide)s are often characterized by their viscosityin solution. For purposes of this invention, a preferred viscosity rangeis about 50 to about 2,000,000 centipoise for a 2% aqueous solution at20° C. Preferred poly(ethylene oxide)s are Polyox® 303, Polyox® Coag,Polyox® 301, Polyox® WSR N-60K, Polyox® WSR 1105 and Polyox® WSR N-80,having number average molecular weights of 7 million, 5 million, 4million, 2 million, 900,000 and 200,000, respectively, all products ofUnion Carbide Chemicals and Plastics Company Inc. of Danbury, Conn.,USA.

Polysaccharide gums, both natural and modified (semi-synthetic) can beused. Examples are dextran, xanthan gum, gellan gum, welan gum andrhamsan gum. Xanthan gum is preferred.

Crosslinked polyacrylic acids of greatest utility are those whoseproperties are the same as those described above for alkyl-substitutedcellulose and polyalkylene oxide polymers. Preferred crosslinkedpolyacrylic acids are those with a viscosity ranging from about 4,000 toabout 40,000 centipoise for a 1% aqueous solution at 25° C. Threepresently preferred examples are CARBOPOL® NF grades 971P, 974P and 934P(BF Goodrich Co., Specialty Polymers and Chemicals Div., Cleveland,Ohio, USA). Further examples are polymers known as WATER LOCK®, whichare starch/acrylates/acrylamide copolymers available from GrainProcessing Corporation, Muscatine, Iowa, USA.

Suitable polymers also include naturally occurring hydrophilic polymerssuch as, by way of example, proteins such as collagen, fibronectin,albumins, globulins, fibrinogen, fibrin and thrombin; aminatedpolysaccharides, particularly the glycosaminoglycans, e.g., hyaluronicacid, chitin, chondroitin sulfate A, B, or C, keratin sulfate,keratosulfate and heparmn; guar gum; xanthan gum; carageenan; alginates;pectin; and activated polysaccharides such as dextran and starches.

The aforementioned list of polymers is not exhaustive, and a variety ofother synthetic hydrophilic polymers may be used, as will be appreciatedby those skilled in the art.

The polymer may include biodegradable segments and blocks, eitherdistributed throughout the polymer's molecular structure or present as asingle block, as in a block copolymer. Biodegradable segments are thosethat degrade so as to break covalent bonds. Typically, biodegradablesegments are segments that are hydrolyzed in the presence of water.Biodegradable segments may be composed of small molecular segments suchas ester linkages, anhydride linkages, ortho ester linkages, orthocarbonate linkages, amide linkages, phosphonate linkages, etc.

Any polymer or polymers of the matrix may also be crosslinked, with thedegree of crosslinking directly affecting the rate of polymer swellingas well as the erosion rate. That is, a polymer having a higher degreeof crosslinking will exhibit less swelling and slower erosion than apolymer having a lower degree of crosslinking. Crosslinked polymers maybe prepared using the above-mentioned exemplary polymers usingconventional crosslinking procedures (e.g., chemical crosslinking withan added crosslinking agent, photolytically induced crosslinking, etc.),or the polymers may be obtained commercially in crosslinked form.

The water-swellable polymers can be used individually or in combination.Certain combinations will often provide a more controlled release of thedrug than their components when used individually. Examples include, butare not limited to, the following: a cellulosic polymer combined with agum, such as hydroxyethylcellulose or hydroxypropylcellulose combinedwith xanthan gum; a polyalkylene oxide combined with a gum, such aspoly(ethylene oxide) combined with xanthan gum; and a polyalkylene oxidecombined with a cellulosic polymer, such as poly(ethylene oxide)combined with hydroxyethylcellulose, hydroxypropylcellulose, and/orhydroxypropyl methylcellulose.

Combinations of different poly(ethylene oxide)s are also contemplated,with polymers of different molecular weights contributing to differentdosage form characteristics. For example, a very high molecular weightpoly(ethylene oxide) such as Polyox® 303 (with a number averagemolecular weight of 7 million) or Polyox® Coag (with a number averagemolecular weight of 5 million) may be used to significantly enhancediffusion relative to disintegration release by providing high swellingas well as tablet integrity. Incorporating a lower molecular weightpoly(ethylene oxide) such as Polyox® WSR N-60K (number average molecularweight approximately 2 million) with Polyox® 303 and/or Polyox® Coagincreases disintegration rate relative to diffusion rate, as the lowermolecular weight polymer reduces swelling and acts as an effectivetablet disintegrant. Incorporating an even lower molecular weightpoly(ethylene oxide) such as Polyox® WSR N-80 (number average molecularweight approximately 200,000) further increases disintegration rate.

The hydrophilicity and water swellability of the polymers used hereincause the drug-containing matrices to swell in size in the gastriccavity due to ingress of water in order to achieve a size that will beretained in the stomach when introduced during the fed mode. Thesequalities also cause the matrices to become slippery, which providesresistance to peristalsis and further promotes their retention in thestomach. The release rate of a drug from the matrix is primarilydependent upon the rate of water imbibition and the rate at which thedrug dissolves and diffuses from the swollen polymer, which in turn isrelated to the solubility and dissolution rate of the drug, the drugparticle size and the drug concentration in the matrix.

The amount of polymer relative to the drug can vary, depending on thedrug release rate desired and on the polymer, its molecular weight, andexcipients that may be present in the formulation. Preferably, theamount of polymer is effective to provide a desired extended releaseperiod within the fed stomach, such that the time to reach maximumplasma concentration (t_(max)) a is at least one hour longer, preferablyat least two hours longer, and most preferably at least three hourslonger, than that observed with immediate release dosage forms intendedto deliver the same drug. In this way, the required doses per day can bereduced. However, a competing consideration is the desirability ofreleasing the majority of drug in the stomach and upper G.I. tract,meaning that the amount of polymer should also be effective to releasemost of or even all the drug before the drug and/or dosage form passesinto the lower intestinal tract. Ideally, at least 75 wt. %, preferablyat least 85 wt. %, and more preferably at least 90 wt. % of the drug isreleased to the stomach, duodenum, and upper intestinal tract within twoto ten hours, preferably within four to nine hours, more preferablywithin four to six hours, after ingestion. Both goals here can be easilyattained with active agents such as ciprofloxacin that exhibit theirtherapeutic effect for a time period extending beyond their half-life,meaning that only a modest extension of the drug delivery period isnecessary to reduce the number of doses per day, e.g., from atwice-a-day dosing regimen to a once-a-day dosing regimen.

It has now been found that higher molecular weight polymers arepreferred to provide a desired extended release profile using thepresent dosage forms. Suitable molecular weights are generally in therange of about 5,000 to about 20,000,000. For sparingly soluble drugs,the polymers have molecular weights preferably in the range of about5,000 to about 8,000,000, more preferably in the range of about 10,000to about 5,000,000. For water-soluble drugs, the polymers preferablyhave molecular weights of at least about 10,000, but the molecularweight used will vary with the selected polymer. For example, forhydroxypropyl methylcellulose, the minimum molecular weight may be aslow as 10,000, while for polyethylene oxide)s the molecular weight maybe far higher, on the order of 2,000,000 or more.

IV. Active Agents

The dosage forms of the present invention are effective for thecontinuous, controlled administration of drugs that are capable ofacting either locally within the gastrointestinal tract, or systemicallyby absorption into circulation via the gastrointestinal mucosa.Gastric-retentive dosage forms such as those disclosed and claimedherein are particularly useful for the delivery of drugs that arerelatively insoluble, are ionized within the gastrointestinal tract, orrequire active transport.

Preferred active agents for administration using the present dosageforms are those that have increased aqueous solubility in more acidicmedia, i.e., those whose aqueous solubility increases with decreasingpH. For example, a relatively hydrophobic basic drug that exists in theform of a free base at about neutral pH but which is ionized at a lowerpH could be expected to exhibit the aforementioned solubility profile.The aqueous solubility of the active agent in an acidic environment isnot necessarily high; the active agent may in fact be only slightlysoluble at low pH, so long as it becomes even less soluble, andpreferably substantially insoluble, in water at higher pH. The activeagents may be acidic, basic, or in the form of an acid addition salt.Generally, the pH at which the pH at which the drug becomessubstantially insoluble is in the range of 5 to 8, generally 5 to 7.5

The active agent administered may be any compound that is suitable fororal drug administration; examples of the various classes of activeagents that can be administered using the present dosage forms include,but are not limited to: analgesic agents; anesthetic agents;antiarthritic agents; respiratory drugs; anticancer agents;anticholinergics; anticonvulsants; antidepressants; antidiabetic agents;antidiarrheals; antihelminthics; antihistamines; antihyperlipidemicagents; antihypertensive agents; anti-infective agents such asantibiotics and antiviral agents; antiinflammatory agents; antimigrainepreparations; antinauseants; antineoplastic agents; antiparkinsonismdrugs; antipruritics; antipsychotics; antipyretics; antispasmodics;antitubercular agents; antiulcer agents and other gastrointestinallyactive agents; antiviral agents; anxiolytics; appetite suppressants:attention deficit disorder (ADD) and attention deficit hyperactivitydisorder (ADHD) drugs; cardiovascular preparations including calciumchannel blockers, CNS agents, and vasodilators; beta-blockers andantiarrhythmic agents; central nervous system stimulants; cough and coldpreparations, including decongestants; diuretics; genetic materials;herbal remedies; hormonolytics; hypnotics; hypoglycemic agents;immunosuppressive agents; leukotriene inhibitors; mitotic inhibitors;muscle relaxants; narcotic antagonists; nutritional agents, such asvitamins, essential amino acids and fatty acids; parasympatholytics;peptide drugs; psychostimulants; sedatives; steroids; sympathomimetics;and tranquilizers.

Commonly known drugs that are substantially insoluble or only slightlysoluble in water include, by way of example, the following:

Gastrointestinally Active Agents.

Gastrointestinally active agents are particularly preferred drugs thatcan be administered using the present dosage forms. These types of drugsinclude agents for inhibiting gastric acid secretion, such as the H₂receptor antagonists cimetidine, ranitidine, famotidine, and nizatidine,the H⁺, K⁺-ATPase inhibitors (also referred to as “proton pumpinhibitors”) omeprazole and lansoprazole, and antacids such as calciumcarbonate, aluminum hydroxide, and magnesium hydroxide. Also includedwithin this general group are agents for treating infection withHelicobacter pylori (H. pylori), such as metronidazole. tinidazole,amoxicillin, clarithromycin, tetracycline, thiamphenicol, and bismuthcompounds (e.g., bismuth subcitrate and bismuth subsalicylate). Othergastrointestinally active agents administrable using the present dosageforms include, but are not limited to, pentagastrin, carbenoxolone,sulfated polysaceharides such as sucralfate, prostaglandins such asmisoprostol, and muscarinic antagonists such as pirenzepine andtelenzepine. Additionally included are antidiarrheal agents, antiemeticagents and prokinetic agents such as ondansetron, granisetron,metoclopramide, chlorpromazine, perphenazine, prochlorperazine,promethazine, thiethylperazine, triflupromazine, domperidone,trimethobenzamide, cisapride, motilin, loperamide, diphenoxylate, andoctreotide.

Anti-Microbial Agents.

These include: quinolone antibiotics such as nalidixic acid, andparticularly fluorinated quinolone antibiotics such as ciprofloxacin,clinafloxacin, enoxacin, gatifloxacin, grepafloxacin, levofloxacin,lomefloxacin, moxifloxacin, norfloxacin, ofloxacin, pefloxacin,sparfloxacin, and trovafloxacin; tetracycline antibiotics and relatedcompounds (chlortetracycline, oxytetracycline, demeclocycline,methacycline, doxycycline, minocycline, rolitetracycline); macrolideantibiotics such as erythromycin, clarithromycin, and azithromycin;streptogramin antibiotics such as quinupristin and dalfopristin;beta-lactam antibiotics, including penicillins (e.g., penicillin G,penicillin VK), antistaphylococcal penicillins (e.g., cloxacillin,dicloxacillin, nafcillin, and oxacillin), extended spectrum penicillins(e.g., aminopenicillins such as ampicillin and amoxicillin, and theantipseudomonal penicillins such as carbenicillin), and cephalosporins(e.g., cefadroxil, cefepime, cephalexin, cefazolin, cefoxitin,cefotetan, cefuroxime, cefotaxime, ceftazidime, and ceftriaxone), andcarbapenems such as imipenem, meropenem and aztreonam; aminoglycosideantibiotics such as streptomycin, gentamicin, tobramycin, amikacin, andneomycin; glycopeptide antibiotics such as teicoplanin; sulfonamideantibiotics such as sulfacetamide, sulfabenzamide, sulfadiazine,sulfadoxine, sulfamerazine, sulfamethazine, sulfamethizole, andsulfamethoxazole; anti-mycobacterials such as isoniazid, rifampin,rifabutin, ethambutol, pyrazinamide, ethionamide, aminosalicylic, andcycloserine; systemic antifungal agents such as itraconazole,ketoconazole, fluconazole, and amphotericin B; antiviral agents such asacyclovir, famcicylovir, ganciclovir, idoxuridine, sorivudine,trifluridine, valacyclovir, vidarabine, didanosine, stavudine,zalcitabine, zidovudine, amantadine, interferon alpha, ribavirin andrimantadine; and miscellaneous antimicrobial agents such aschioramphenicol, spectinomycin, polymyxin B (colistin), bacitracin,nitrofurantoin, methenamine mandelate and methenamine hippurate.

Anti-Diabetic Agents.

These include, by way of example, acetohexamide, chlorpropamide,ciglitazone, gliclazide, glipizide, glucagon, glyburide, miglitol,pioglitazone, tolazamide, tolbutamide, triampterine, and troglitazone.

Analgesics.

Non-opioid analgesic agents include apazone, etodolac, difenpiramide,indomethacin, meclofenamate, mefenamic acid, oxaprozin, phenylbutazone,piroxicam, and tolmetin; opioid analgesics include alfentanil,buprenorphine, butorphanol, codeine, drocode, fentanyl, hydrocodone,hydromorphone, levorphanol, meperidine, methadone, morphine, nalbuphine,oxycodone, oxymorphone, pentazocine, propoxyphene, sufentanil, andtramadol.

Anti-Inflammatory Agents.

Anti-inflammatory agents include the nonsteroidal anti-inflammatoryagents, e.g., the propionic acid derivatives as ketoprofen,flurbiprofen, ibuprofen, naproxen, fenoprofen, benoxaprofen, indoprofen,pirprofen, carprofen, oxaprozin, pranoprofen, suprofen, alminoprofen,butibufen, and fenbufen; apazone; diclofenac: difenpiramide; diflunisal;etodolac; indomethacin; ketorolac: meclofenamate; nabumetone;phenylbutazone; piroxicam; sulindac; and tolmetin. Steroidalanti-inflammatory agents include hydrocortisone,hydrocortisone-21-monoesters (e.g., hydrocortisone-21-acetate,hydrocortisone-21-butyrate, hydrocortisone-21-propionate,hydrocortisone-21-valerate, etc.), hydrocortisone-17,21-diesters (e.g.,hydrocortisone-17,21-diacetate, hydrocortisone-17-acetate-21-butyrate,hydrocortisone-17,21-dibutyrate, etc.), alclometasone, dexamethasone,flumethasone, prednisolone, and methylprednisolone.

Anti-Convulsant Agents.

Suitable anti-convulsant (anti-seizure) drugs include, by way ofexample, azetazolamide, carbamazepine, clonazepam, clorazepate,ethosuximide, ethotoin, felbamate, lamotrigine, mephenyloin,mephobarbital, phenyloin, phenobarbital, primidone, trimethadione,vigabatrin, topiramate, and the benzodiazepines. Benzodiazepines, as iswell known, are useful for a number of indications, including anxiety,insomnia, and nausea.

CNS and Respiratory Stimulants.

CNS and respiratory stimulants also encompass a number of active agents.These stimulants include, but are not limited to, the following:xanthines such as caffeine and theophylline; amphetamines such asamphetamine, benzphetamine hydrochloride, dextroamphetamine,dextroamphetamine sulfate, levamphetamine, levamphetamine hydrochloride,methamphetamine, and methamphetamine hydrochloride; and miscellaneousstimulants such as methylphenidate, methylphenidate hydrochloride,modafinil, pemoline, sibutramine, and sibutramine hydrochloride.

Neuroleptic Agents.

Neuroleptic drugs include antidepressant drugs, antimanic drugs, andantipsychotic agents, wherein antidepressant drugs include (a) thetricyclic antidepressants such as amoxapine, amitriptyline,clomipramine, desipramine, doxepin, imipramine, maprotiline,nortriptyline, protriptyline, and trimipramine, (b) the serotoninreuptake inhibitors citalopram, fluoxetine, fluvoxamine, paroxetine,sertraline, and venlafaxine, (c) monoamine oxidase inhibitors such asphenelzine, tranylcypromine, and (−)-selegiline, and (d) other,“atypical” antidepressants such as nefazodone, trazodone andvenlafaxine, and wherein antimanic and antipsychotic agents include (a)phenothiazines such as acetophenazine, acetophenazine maleate,chlorpromazine, chlorpromazine hydrochloride, fluphenazine, fluphenazinehydrochloride, fluphenazine enanthate, fluphenazine decanoate,mesoridazine, mesoridazine besylate, perphenazine, thioridazine,thioridazine hydrochloride, trifluoperazine, and trifluoperazinehydrochloride. (b) thioxanthenes such as chlorprothixene, thiothixene,and thiothixene hydrochloride, and (c) other heterocyclic drugs such ascarbamazepine, clozapine, droperidol, haloperidol, haloperidoldecanoate, loxapine succinate, molindone, molindone hydrochloride,olanzapine, pimozide, quetiapine, risperidone, and sertindole.

Hypnotic agents and sedatives include clomethiazole, ethinamate,etomidate, glutethimide, meprobamate, methyprylon, zolpidem, andbarbiturates (e.g., amobarbital, apropbarbital, butabarbital,butalbital, mephobarbital, methohexital, pentobarbital, phenobarbital,secobarbital, thiopental).

Anxiolytics and tranquilizers include benzodiazepines (e.g., alprazolam,brotizolam, chlordiazepoxide, clobazam, clonazepam, clorazepate,demoxepam, diazepam, estazolam, flumazenil, flurazepam, halazepam,lorazepam, midazolam, nitrazepam, nordazepam, oxazepam, prazepam,quazepam, temazepam, triazolam), buspirone, chlordiazepoxide, anddroperidol.

Anticancer Agents, Including Antineoplastic Agents:

Paclitaxel, docetaxel, camptothecin and its analogues and derivatives(e.g., 9-aminocamptothecin, 9-nitrocamptothecin,10-hydroxy-camptothecin, irinotecan, topotecan, 20-O-β-glucopyranosylcamptothecin), taxanes (baccatins, cephalomannine and theirderivatives), carboplatin, cisplatin, interferon-α_(2A),interferon-α_(2B), interferon-α_(N3) and other agents of the interferonfamily5′, levamisole, altretamine, cladribine, tretinoin, procarbazine,dacarbazine, gemcitabine, mitotane, asparaginase, porfimer, mesna,amifostine, mitotic inhibitors including podophyllotoxin derivativessuch as teniposide and etoposide and ymca alkaloids such as vinorelbine,vincristine and vinblastine.

Antihyperlipidemic Agents.

Lipid-lowering agents, or “hyperlipidemic” agents,” include HMG-CoAreductase inhibitors such as atorvastatin, simvastatin, pravastatin,lovastatin and cerivastatin, and other lipid-lowering agents such asclofibrate, fenofibrate, gemfibrozil and tacrine.

Anti-Hypertensive Agents.

These include amlodipine, benazepril, darodipine, dilitazem, diazoxide,doxazosin, enalapril, eposartan, losartan, valsartan, felodipine,fenoldopam, fosinopril, guanabenz, guanadrel, guanethidine, guanfacine,hydralazine, metyrosine, minoxidil, nicardipine, nifedipine,nisoldipine, phenoxybenzamine, prazosin, quinapril, reserpine, andterazosin.

Cardiovascular Preparations.

Cardiovascular preparations include, by way of example, angiotensinconverting enzyme (ACE) inhibitors such as enalapril.1-carboxymethyl-3-1-carboxy-3-phenyl-(1S)-propylamino-2,3,4,5-tetrahydro-1H-(3S)-1-benzazepine-2-one,3-(5-amino-1-carboxy-1S-pentyl)amino-2,3,4,5-tetrahydro-2-oxo-3S-1H-1-benzazepine-1-aceticacid or3-(1-ethoxycarbonyl-3-phenyl-(1S)-propylamino)-2,3,4,5-tetrahydro-2-oxo-(3S)-benzazepine-1-aceticacid monohydrochloride; cardiac glycosides such as digoxin anddigitoxin; inotropes such as amrinone and milrinone; calcium channelblockers such as verapamil, nifedipine, nicardipene, felodipine,isradipine, nimodipine, bepridil, amlodipine and diltiazem;beta-blockers such as atenolol, metoprolol; pindolol, propafenone,propranolol, esmolol, sotalol, timolol, and acebutolol; antiarrhythmicssuch as moricizine, ibutilide, procainamide, quinidine, disopyramide,lidocaine, phenyloin, tocainide, mexiletine, flecainide, encainide,bretylium and amiodarone; and cardioprotective agents such asdexrazoxane and leucovorin; and vasodilators such as nitroglycerin; anddiuretic agents such as hydrochlorothiazide, furosemide, bumetanide,ethacrynic acid, torsemide, azosemide, muzolimine, piretanide, andtripamide.

Anti-Viral Agents.

Antiviral agents that can be delivered using the present dosage formsinclude the antiherpes agents acyclovir, famciclovir, foscamet,ganciclovir, idoxuridine, sorivudine, trifluridine, valacyclovir, andvidarabine; the antiretroviral agents didanosine, stavudine,zalcitabine, and zidovudine; and other antiviral agents such asamantadine, interferon alpha, ribavirin and rimantadine.

Sex Steroids.

The sex steroids include, first of all, progestogens such asacetoxypregnenolone, allylestrenol, anagestone acetate, chlormadinoneacetate, cyproterone, cyproterorie acetate, desogestrel,dihydrogesterone, dimethisterone, ethisterone (17α-ethinyltestosterone),ethynodiol diacetate, flurogestone acetate, gestadene,hydroxyprogesterone, hydroxyprogesterone acetate, hydroxyprogesteronecaproate, hydroxymethylprogesterone, hydroxymethylprogesterone acetate,3-ketodesogestrel, levonorgestrel, lynestrenol, medrogestone,medroxyprogesterone acetate, megestrol, megestrol acetate, melengestrolacetate, norethindrone, norethindrone acetate, norethisterone,norethisterone acetate, norethynodrel, norgestimate, norgestrel,norgestrienone, normethisterone, and progesterone. Also included withinthis general class are estrogens. e.g.: estradiol (i.e.,1,3,5-estratriene-3.17β-diol, or “17β-estradiol”) and its esters,including estradiol benzoate, valerate, cypionate, heptanoate,decanoate, acetate and diacetate; 17α-estradiol; ethinylestradiol (i.e.,17α-ethinylestradiol) and esters and ethers thereof, includingethinylestradiol 3-acetate and ethinylestradiol 3-benzoate: estriol andestriol succinate; polyestrol phosphate; estrone and its esters andderivatives, including estrone acetate, estrone sulfate, and piperazineestrone sulfate; quinestrol; mestranol; and conjugated equine estrogens.Androgenic agents, also included within the general class of sexsteroids, are drugs such as the naturally occurring androgensandrosterone, androsterone acetate, androsterone propionate,androsterone benzoate, androstenediol, androstenediol-3-acetate,androstenediol-17-acetate, androstenediol-3,17-diacetate,androstenediol-17-benzoate, androstenediol-3-acetate-17-benzoate,androstenedione, dehydroepiandrosterone (DHEA; also termed“prasterone”), sodium dehydroepiandrosterone sulfate,4-dihydrotestosterone (DHT; also termed “stanolone”),5α-dihydrotestosterone, dromostanolone, dromostanolone propionate,ethylestrenol, nandrolone phenpropionate, nandrolone decanoate,nandrolone furylpropionate, nandrolone cyclohexanepropionate, nandrolonebenzoate, nandrolone cyclohexanecarboxylate, oxandrolone, stanozolol andtestosterone; pharmaceutically acceptable esters of testosterone and4-dihydrotestosterone, typically esters formed from the hydroxyl grouppresent at the C-17 position, including, but not limited to, theenanthate, propionate, cypionate, phenylacetate, acetate, isobutyrate,buciclate, heptanoate, decanoate, undecanoate, caprate and isocaprateesters; and pharmaceutically acceptable derivatives of testosterone suchas methyl testosterone, testolactone, oxymetholone and fluoxymesterone.

Muscarinic Receptor Agonists and Antagonists.

Muscarinic receptor agonists include, by way of example: choline esterssuch as acetylcholine, methacholine, carbachol, bethanechol(carbamylmethylcholine), bethanechol chloride, cholinomimetic naturalalkaloids and synthetic analogs thereof, including pilocarpine,muscarine, McN-A-343, and oxotremorine. Muscarinic receptor antagonistsare generally belladonna alkaloids or semisynthetic or synthetic analogsthereof, such as atropine, scopolamine, homatropine, homatropine methylbromide, ipratropium, methantheline, methscopolamine and tiotropium.

Peptide Drugs.

Peptidyl drugs include the peptidyl hormones activin, amylin,angiotensin, atrial natriuretic peptide (ANP), calcitonin, calcitoningene-related peptide, calcitonin N-terminal flanking peptide, ciliaryneurotrophic factor (CNTF), corticotropin (adrenocorticotropin hormone,ACTH), corticotropin-releasing factor (CRF or CRH), epidermal growthfactor (EUF), follicle-stimulating hormone (FSH), gastrin, gastrininhibitory peptide (alP), gastrin-releasing peptide,gonadotropin-releasing factor (GnRF or GHRH), growth hormone releasingfactor (GRF, GRH), human chorionic gonadotropin (hCH), inhibin A,inhibin B, insulin, luteinizing hormone (LH), luteinizinghormone-releasing hormone (LHRH), a-melanocyte-stimulating hormone,$3-melanocyte-stimulating hormone, y-melanocyte-stimulating hormone,melatonin, motilin, oxytocin (pitocin), pancreatic polypeptide,parathyroid hormone (PTH), placental lactogen, prolactin (PRL),prolactin-release inhibiting factor (PIF), prolactin-releasing factor(PRF), secretin, somatotropin (growth hormone, GH), somatostatin (SW,growth hormone-release inhibiting factor, GIF), thyrotropin(thyroid-stimulating hormone, TSH), thyrotropin-releasing factor (TRH orTRF), thyroxine, vasoactive intestinal peptide (VIP), and vasopressin.Other peptidyl drugs are the cytokines, e.g., colony stimulating factor4, heparin binding neurotrophic factor (HBNF), interferon-α, interferonα-2a, interferon α-2b, interferon α-n3, interferon-β, etc.,interleukin-1, interleukin-2, interleukin-3, interleukin-4,interleukin-5, interleukin-6, etc., tumor necrosis factor, tumornecrosis factor-ct, granuioycte colony-stimulating factor (G-CSF),granulocytemacrophage colony-stimulating factor (GM-CSF), macrophagecolony-stimulating factor, midkine (MD), and thymopoietin. Still otherpeptidyl drugs that can be advantageously delivered using the presentsystems include endorphins (e.g., dermorphin, dynorphin, α-endorphin,β-endorphin, γ-endorphin, σ-endorphin, [Leu⁵]enkephalin,[Met⁵]enkephalin, substance P), kinins (e.g., bradykinin, potentiator B,bradykinin potentiator C, kallidin), LHRH analogues (e.g., buserelin,deslorelin, fertirelin, goserelin, histrelin, leuprolide, lutrelin,nafarelin, tryptorelin), and the coagulation factors, such asα₁-antitrypsin, α₂-macroglobulin, antithrombin III, factor I(fibrinogen), factor II (prothrombin), factor III (tissue prothrombin),factor V (proaccelerin), factor VII (proconvertin), factor VIII(antihemophilic globulin or AHG), factor IX (Christmas factor, plasmathromboplastin component or PTC), factor X (Stuart-Power factor), factorXI (plasma thromboplastin antecedent or PTA), factor XII (Hagemanfactor), heparin cofactor II, kallikrein, plasmin, plasminogen,prekallikrein, protein C, protein S, and thrombomodulin and combinationsthereof.

Genetic material may also be delivered using the present dosage forms,e.g., nucleic acids, RNA. DNA, recombinant RNA, recombinant DNA,antisense RNA, antisense DNA, ribozymes, ribooligonucleotides,deoxyribonucleotides, antisense ribooligonucleotides, and antisensedeoxyribooligonucleotides. Representative genes include those encodingfor vascular endothelial growth factor, fibroblast growth factor. Bcl-2,cystic fibrosis transmembrane regulator, nerve growth factor, humangrowth factor, erythropoietin, tumor necrosis factor, and interleukin-2,as well as histocompatibility genes such as HLA-B7.

In contrast to many erodible dosage forms, the low variability of thepresent dosage forms is particularly important for poorly soluble drugssuch as phenyloin and carbamazepine, both anticonvulsant drugs used inthe treatment of epilepsy, as noted above, and for which, due to widevariation in drug absorption from patient to patient, doctors must nowtitrate their patients individually to find a proper (i.e., safe andeffective) dosage regimen. In this regard, the dosage forms of theinvention are useful for more consistent delivery of sparingly solubledrugs that have a narrow therapeutic index, i.e., drugs for which thetoxic dose is not significantly higher than the effective dose.

The dosage forms of the present invention are particularly useful fordelivering drugs directly into the stomach for an extended period oftime, for example, when the drug is preferentially absorbed in the smallintestine (e.g., ciprofloxacin), or for providing continuous, local-only(non-systemic) action, for example, when the drug is calcium carbonate,and which when incorporated into the dosage forms of the presentinvention becomes a non-systemic, controlled-release antacid. The dosageforms are also useful for delivering drugs continuously to the stomachthat are only soluble in that portion of the gastrointestinal tract. Forinstance, the dosage forms of the present invention are useful for thedelivery of calcium carbonate or other calcium salts intended to be usedas an antacid or as a dietary supplement to prevent osteoporosis.Calcium salts are soluble in the stomach but not in the remainder of theG.I. tract, as a result of the presence of stomach acid. Withconventional dosage forms, the dwell time of the delivered agent in thestomach is limited usually to only about 20 to 40 minutes, which, inturn, results in a calcium availability of only about 15 to 30%. As aconsequence, extremely large dosage forms (2.5 grams), which aredifficult for patients to swallow, are commonly utilized. In contrast,by providing controlled delivery for about 4 to 9 hours, plus gastricretention of from about 2 to 12, preferably 4 to 9 hours, mostpreferably about 4 to 6 hours, the dosage forms of the present inventionassure more complete bioavailability of elemental calcium from theadministered drug, i.e., calcium carbonate. This results in a greaterlikelihood of patients receiving the intended dose and, also, avoids theneed for impractically large dosage forms.

The dosage forms of the present invention are also useful for deliveringdrugs to treat local disorders of the stomach, such as those that areeffective for eradicating Helicobacter pylori (H. pylori) from thesubmucosal tissue of the stomach, to treat stomach and duodenal ulcers,to treat gastritis and esophagitis and to reduce risk of gastriccarcinoma. The dosage forms of the present invention are particularlyuseful for the foregoing indications because they provide enhancedgastric retention and prolonged release. In a preferred such embodiment,a dosage form of the invention will comprise a combination of (a)bismuth (e.g., as bismuth subsalicylate), (b) an antibiotic such astetracycline, amoxicillin, thiamphenicol, or clarithromycin, and (c) aproton pump inhibitor, such as omeprazole. A combination of bismuthsubsalicylate, thiamphenicol and omeprazole is a particularly preferredcombination that may be delivered using the dosage forms of the presentinvention for the eradication of H. pylori.

Drugs delivered from the gastric-retentive, controlled delivery dosageforms of the invention continuously bathe the stomach and upper part ofthe small intestine—in particular, the duodenum—for many hours. Thesesites, particularly the upper region of the small intestine, are thesites of most efficient absorption for many drugs. By continuallysupplying the drug to its most efficient site of absorption, the dosageforms of the present invention allow for more effective oral use of manydrugs.

Since the dosage forms of the present invention provide the drug bymeans of a continuous delivery instead of the pulse-entry deliveryassociated with conventional dosage forms, two particularly significantbenefits result from their use: (1) a reduction in side effects from thedrug(s); and (2) an ability to effect treatment with less frequentadministration of the drug(s) being used. For instance, whenadministered in a conventional dosage form, the sparingly soluble drug,ciprofloxacin, an antibiotic administered to treat bacterial infectionssuch as urinary tract infections, is currently given two times daily andmay be frequently accompanied by gastrointestinal side effects such asdiarrhea. However, using the dosage forms of the present invention, thenumber of daily doses can be decreased to one with a lower incidence ofside effects.

The invention is not, however, limited to dosage forms for deliveringpoorly soluble drugs. Drugs having moderate to substantial aqueoussolubility can also be delivered using the present dosage forms. Ifnecessary, they may be encased in a protective vesicle or coated with aprotective coating so as to prevent a too rapid release. Preferred suchdrugs include, without limitation, metformin hydrochloride, vancomycinhydrochloride, captopril, enalopril or its salts, erythromycinlactobionate, ranitidine hydrochloride, sertraline hydrochloride,ticlopidine hydrochloride, amoxicillin, cefuroxime axetil, cefaclor,clindamycin, doxifluridine, gabapentin, tramadol, fluoxetinehydrochloride, acyclovir, levodopa, ganciclovir, bupropion, lisinopril,losartan, and esters of ampicillin. Particularly preferred such drugsare metformin hydrochloride, gabapentin, lisinopril, enalopril,losartan, and sertraline hydrochloride.

Any of the aforementioned active agents may also be administered incombination using the present dosage forms. Examples of particularlyimportant drug combination products include, but are not limited to, anACE inhibitor or an angiotensin II antagonist in combination with adiuretic. Specific examples of ACE inhibitors are captopril, lisinopril,or enalopril, and examples of diuretics include triampterine,furosemide, bumetanide, and hydrochlorothiazide. Alternatively, eitherof these diuretics can advantageously be used in combination with abeta-adrenergic blocking agent such as propranolol, timolol ormetoprolol. These particular combinations are useful in cardiovascularmedicine, and provide advantages of reduced cost over separateadministrations of the different drugs, plus the particular advantage ofreduced side effects and enhanced patient compliance. For example, ithas been shown that small doses of a diuretic plus small doses of eitheran ACE inhibitor or a beta blocker provide the additive effects oflowering blood pressure without the additive side effects of the twotogether.

Particularly preferred drugs for administration using the present dosageforms include, but are not limited to, furosemide, gabapentin, losartan,budesonide, and the antibiotics ciprofloxacin and minocycline. The drugsmay be in the form of salts, esters or other derivatives. For example,ciprofloxacin and minocycline may be incorporated as acid additionsalts, such as ciprofloxacin hydrochloride and minocyclinehydrochloride, respectively.

Drug loading may be expressed in terms of the volume fraction of drugrelative to the entire dosage form, or, if the dosage form is a bilayeror trilayer tablet, in terms of the volume fraction of drug relative tothe erodible layer in which it is contained. The drug loading in thepresent dosage forms is in the range of about 0.01% to 80%, but ispreferably relatively high, i.e., at least about 60%, preferably in therange of about 60% to 80%, such that the rate of erosion is essentiallydrug-controlled.

V. Dosage Forms, Protective Vesicles and Coatings

The formulations of this invention are typically in the form ofmatrix/active agent tablets, or matrix/active agent particles compressedinto tablets. Other formulations contain matrix/active agent particlesin capsules. The encapsulating material should be highly soluble so thatthe particles are freed and rapidly dispersed in the stomach after thecapsule is ingested. Such dosage forms are prepared using conventionalmethods known to those in the field of pharmaceutical formulation anddescribed in the pertinent texts, e.g., in Remington, cited supra.Tablets and capsules represent the most convenient oral dosage forms, inwhich cases solid pharmaceutical carriers are employed.

Tablets may be manufactured using standard tablet processing proceduresand equipment. One method for forming tablets is by direct compressionof a particulate composition, with the individual particles of thecomposition comprised of a matrix of a biocompatible, hydrophilic,erodible polymer having the active agent incorporated therein, alone orin combination with one or more carriers, additives, or the like. As analternative to direct compression, tablets can be prepared usingwet-granulation or dry-granulation processes. Tablets may also be moldedrather than compressed, starting with a moist or otherwise tractablematerial, and using injection or compression molding techniques usingsuitable molds fitted to a compression unit. Tablets may also beprepared by extrusion in the form of a paste, into a mold, or to providean extrudate to be “cut” into tablets. However, compression andgranulation techniques are preferred, with direct compressionparticularly preferred.

Tablets prepared for oral administration according to the invention, andmanufactured using direct compression, will generally contain othermaterials such as binders, lubricants, disintegrants, fillers,stabilizers, solubilizers, emulsifiers, surfactants, complexing agents,coloring agents, and the like. Binders are used to impart cohesivequalities to a tablet, and thus ensure that the tablet remains intactafter compression. Suitable binder materials include, but are notlimited to, starch (including corn starch and pregelatinized starch),gelatin, sugars (including sucrose, glucose, dextrose and lactose),polyethylene glycol, waxes, and natural and synthetic gums, e.g., acaciasodium alginate, polyvinylpyrrolidone, cellulosic polymers (includinghydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, microcrystalline cellulose, ethyl cellulose, hydroxyethylcellulose, and the like), and Veegum. Lubricants are used to facilitatetablet manufacture, promoting powder flow and preventing particlecapping (i.e., particle breakage) when pressure is relieved. Usefullubricants are magnesium stearate (in a concentration of from 0.25% to3% by weight, preferably from about 1.5% to 2.5% by weight), calciumstearate, stearic acid, and hydrogenated vegetable oil (preferablycomprised of hydrogenated and refined triglycerides of stearic andpalmitic acids at about 1% to 5% by weight, most preferably less thanabout 2% by weight). Disintegrants are used to facilitate disintegrationof the tablet, thereby increasing the erosion rate relative to thedissolution rate, and are generally starches, clays, celluloses, algins,gums, or crosslinked polymers (e.g., crosslinked polyvinyl pyrrolidone).Fillers include, for example, materials such as silicon dioxide,titanium dioxide, alumina, talc, kaolin, powdered cellulose, andmicrocrystalline cellulose, as well as soluble materials such asmannitol, urea, sucrose, lactose, dextrose, sodium chloride, andsorbitol. Solubility-enhancers, including solubilizers pen Se,emulsifiers, and complexing agents (e.g., cyclodextrins), may also beadvantageously included in the present formulations. Stabilizers, aswell known in the art, are used to inhibit or retard drug decompositionreactions that include, by way of example, oxidative reactions.

As noted above, the active agent/polymer matrix particles of theinvention may also be administered in packed capsules. Suitable capsulesmay be either hard or soft, and are generally made of gelatin, starch,or a cellulosic material, with gelatin capsules preferred. Two-piecehard gelatin capsules are preferably sealed, such as with gelatin bandsor the like. See, for example, Remington: The Science and Practice ofPharmacy, cited supra, which describes materials and methods forpreparing encapsulated pharmaceuticals.

As previously mentioned, the dosage forms of the present invention canadditionally be used to deliver a drug incorporated into a protectivevesicle and/or coated with a protective coating. That is, as explainedin U.S. Pat. No. 5,972,389 to Shell et al., cited supra, water-solubledrugs can be rendered substantially insoluble or only slightly solublewhen incorporated into protective vesicles and/or coated with aprotective coating. Suitable vesicles include, but are not limited to,liposomes and nanoparticles, e.g., nanospheres, nanocapsules andnanocrystals composed of amino acids. Vesicles may also be used tosolubilize drugs that otherwise have limited aqueous solubility.

By incorporating a drug either in a protective vesicle or protectivecoating into the dosage form of the present invention, the benefits ofgastric retention and gradual release to the upper 0.1. tract arecombined with the advantageous properties of the vesicle or coating.Advantageous properties associated with the use of protective vesiclesand coatings include, for example, enhancing drug absorption and/oraltering drug solubility. In this context, the drug in combination witheither agent is continuously and gradually released from thegastric-retentive system to bathe the duodenum and the remainder of thesmall intestine in a prolonged manner which is determined by the rate atwhich the polymer erodes.

Examples of such vesicles include liposomes, which can protect anincorporated drug from the time it leaves the dosage form until itreaches the absorption site. Methods for preparing liposome encapsulateddrug systems are known to and used by those of skill in the art. Ageneral discussion, which includes an extensive bibliography regardingliposomes and methods for their preparation, can be found in “Liposomes,A Practical Approach,” R.R.C New, Ed., 1990. Further examples ofsuitable vesicles include microparticulate systems, which areexemplified by nanoparticles and proteinoid and amino acid microspheresand pharmacosomes. Nanoparticles include, for example, nanospheres,nanocapsules, and nanocrystals. The matrix-like structure of thenanosphere allows the drug to be contained either within the matrix orcoated on the outside. Nanoparticles may also consist of stabilizedsubmicron structures of drug with or without surfactant or polymericadditives. Nanocapsules have a shell of polymeric material and, as withthe nanospheres, the drug can be contained either within the shell orcoated on the outside. Polymers that can be used to prepare thenanoparticles include, but are not limited to, polyacrylamide,poly(alkyl methacrylates), poly(alkyl cyanoacrylates),polyglutaraldehyde, poly(lactide-co-glycolide) and albumin. For detailspertaining to nanoparticle preparation, see, e.g., Allemann, E., et al.,“Drug-Loaded Nanoparticles-Preparation Methods and Drug TargetingIssues,” Eur. J. Pharm. Biopharm. 39(5):173-191, 193.

The dosage forms of the invention may also be formulated as bilayertablets, trilayer tablets, or shell-and-core tablets, with bilayer andtrilayer tablets preferred. In any of these embodiments wherein a dosageform is composed of two or more discrete regions each with differentfunctions or attributes (e.g., a bilayer tablet with one layer beingprimarily swellable, and the other layer being primarily erodible), twoor more drugs can be delivered in two or more different regions (e.g.,layers), where the polymer or polymers in each region are tailored toprovide a dissolution, erosion and/or release profile, taking thesolubility and molecular weight of the drug into account. For example, abilayer tablet may be prepared with one drug incorporated into anerosional layer and a second drug, which may or may not be identical tothe first drug, incorporated into a swelling layer, or a single drug maybe incorporated into an erosional layer, with no active agent in theswelling layer. As another example, a trilayer tablet may be preparedwith a two outer layers containing drug, comprised of a polymer that isprimarily erodible, with a swellable intermediate layer therebetween.The function of the swelling layer is to provide sufficient particlesize throughout the entire period of drug delivery to promote gastricretention in the fed mode. In other embodiments, a drug may be includedin a coating for immediate release.

VI. Dosage and Administration

Different drugs have different biological half-lives, which determinetheir required frequency of administration (once daily, four timesdaily, etc.). Thus, when two or more drugs are co-administered in oneconventional medication unit, an unfavorable compromise is oftenrequired, resulting in an underdose of one drug and an overdose of theother. One of the advantages of the dosage forms of the presentinvention is that they can be used to deliver multiple drugs withoutrequiring such compromises. For example, in an alternative embodiment, aplurality of drug-containing, spherical, spheroidal- orcylindrical-shaped particles are provided, some of the particlescontaining a first drug/polymer composition designed to release thefirst drug at its ideal rate and duration (dose), while other particlescontain a second drug/polymer composition designed to release the seconddrug at its ideal rate and duration. In this embodiment, the polymers orpolymer molecular weight values used for each of the drugs can be thesame or different. Control of the release rate of the differing drugscan also be obtained by combining different numbers of each of thedrug/polymer particles in a common dosage form such as a capsule. Forexample, where two drugs are combined in a capsule made from fiveparticles, three particles would contain one drug and the other twoparticles would contain the other drug.

Furthermore, the invention provides dosage forms of separate particles,each comprising polymers that may erode at different rates. As a result,the dosage forms of the present invention achieve a plurality of drugdelivery rates. For example, the dosage form may comprise threeparticles, the first and second containing a swellable polymer thaterodes and delivers drug over a period of 4 hours, and the thirdcontaining a swellable polymer that erodes and delivers drug over aperiod of 8 hours. In this regard, requisite erosion rates can beachieved by combining polymers of differing erosion rates into a singleparticle.

In addition, the invention provides dosage forms of separate particles,some comprising polymers that swell, but do not erode and somecomprising polymers that swell and erode (with either the same ordiffering erosion rates). As a result, the dosage forms can achieve aplurality of delivery rates. For example, the dosage form may comprisethree particles, the first containing a swellable polymer that deliversdrug over a period of 8 hours, the second containing aswellable/erodible polymer that erodes and delivers drug over a periodof 4 hours, and the third containing a swellable/erodible polymer thaterodes and delivers drug over a period of 6 hours. In this example, thedosage form may contain one, two or three different drugs.

Drugs that are otherwise chemically incompatible when formulatedtogether can be delivered simultaneously via separate swellableparticles contained in a single dosage form. For example, theincompatibility of aspirin and prednisolone can be overcome with adosage form comprising a first swellable particle with one drug and asecond swellable particle with the other. In this manner, the gastricretention and simultaneous delivery of a great number of different drugsis now possible.

The dose of drugs from conventional medication forms is specified interms of drug concentration and administration frequency. In contrast,because the dosage forms of the present invention deliver a drug bycontinuous, controlled release, a dose of medication used in thedisclosed systems is specified by drug release rate and by duration ofrelease. The continuous, controlled delivery feature of the systemallows for (a) a reduction in drug side effects, since only the levelneeded is provided to the patient, and (b) a reduction in the number ofdoses per day.

It is to be understood that while the invention has been described inconjunction with the preferred specific embodiments thereof, that theforegoing description as well as the examples that follow are intendedto illustrate and not limit the scope of the invention. Other aspects,advantages and modifications within the scope of the invention will beapparent to those skilled in the art to which the invention pertains.

All patents, patent applications, and publications mentioned herein arehereby incorporated by reference in their entireties.

Example 1

Drug dosage forms containing ciprofloxacin hydrochloride were preparedin the form of compressed tablets comprised of swellable, erodiblematrix particles with the active agent therein. The matrix particles inthe tablets were formulated so as to contain, in a 950 mg tablet, 582 mgciprofloxacin hydrochloride (equivalent to 500 mg ciprofloxacin), atleast one polyethylene oxide) (number average molecular weight indicatedbelow), magnesium stearate or stearic acid as a lubricant, andoptionally a poly(vinylpyrrolidone) (PVP) binder. The formulation ofeach dosage form was as follows:

Formulation GR-1 (caplet, 8.75×6.35×19.09 mm):

61.35 wt. % ciprofloxacin HCl

14.78 wt. % Polyox® WSR N-60K

21.87 wt. % Polyox® WSR N-80

2 wt. % stearic acid

Formulation GR-2 (caplet, 8.75×6.43×19.09 mm):

61.35 wt. % ciprofloxacin HCl

36.65 wt. % Polyox® WSR N-60K

2 wt. % stearic acid

Formulation GR-3 (oval tablet, 10.05×7.15×18.05 mm):

61.66 wt. % ciprofloxacin HCl

34.43 wt. % Polyox® WSR N-60K

1.9 wt. % poly(vinyl pyrrolidone) (PVP)

2 wt. % magnesium stearate

Immediate Release (IR) Formulation (caplet, 8.75×6.35×19.09 mm):

500 mg ciprofloxacin tablet (Cipro', obtained from Bayer Corporation)

The first two formulations were chosen based on the disintegrationprofile with the expectation that one of the formulations would beretained and deliver ciprofloxacin in the stomach for approximately fourhours. These two formulations, as well as the immediate release tablet,were caplet shaped. The third formulation was in the shape of an ovalinstead of a caplet. The granulation for the oval formulation utilized aPVP binder solution, instead of a Polyox® WSR N-60K binder.

The in vitro release profiles of the dosage forms were evaluated using aUSP Dissolution Test and a USP Disintegration Test. Specifically, eachdosage form was individually tested in a USP Dissolution Apparatus IIusing the USP Dissolution Test described in USP 24-NF 19, Supplement 4,Section 711, using 900 mL of deionized water in a 1-liter vessel,anti-evaporation covers, a paddle speed of 100 rpm, and, for purposes ofcomparison, a paddle speed of 30 rpm. The disintegration test wascarried out in a USP Disintegration Apparatus (55-mm stroke at 30strokes/mm) with fluted disks in place. In vivo pharmacokineticproperties were determined by administering one tablet to each of threehuman subjects within 5 minutes after consumption of a 350-calorie, highfat standardized meal. Ciprofloxacin absorption was measured by urinaryexcretion sampled at time intervals of 0, 1, 2, 4, 6, 8, 10, 12 hoursand all urine voids up to 48 hours after dosing, collected in 12-hourintervals. Approximately 3 hours later, the subjects consumed astandardized lunch.

Table 1 and FIGS. 1 and 2 summarize the in vitro release characteristicsof the four dosage forms.

TABLE 1 In Vitro Release Characteristics RELEASE BY RELEASE BYDISINTEGRATION DISSOLUTION (TIME FOR 90% OF THE (% DRUG DOSAGE FORM TORELEASED @ X DISINTEGRATE, “T₉₀” IN FORMULATION HOURS) HOURS) GR-1 78% @8 hrs 3.3 GR-2 62% @ 8 hrs 5.9 GR-3 50% @ 8 hrs 82% released @ 8 hrs IR(Cipro ®) 12 minutes 3 minutes

Table 2 summarizes the maximum urinary excretion rate of ciprofloxacinfrom the subjects in the in vivo tests. In general, the maximum urinaryexcretion rate was lower for all GR dosage forms in comparison with theimmediate release tablet, and in fact decreased with increasing in vitrorelease profile. On the other hand, the t_(max) for the GR dosage formswas more than double that of the immediate release dosage form,indicative of an in vivo extended release profile.

TABLE 2 Summary of Individual Results IR TABLET GR-1 GR-2   GR-3   Max.Max. Max. Max. Urinary Urinary Urinary Urinary Excretion t_(max)Excretion t_(max) Excretion t_(max) Excretion t_(max) SUBJECT (mg/hr)(hrs) (mg/hr) (hrs) (mg/hr) (hrs) (mg/hr) (hrs) 1 37.4 3.0 42.3 3.0 28.43.0 13.7 3.0 2 33.2 1.5 25.4 5.0 21.5 9.0 13.2 6.5 3 36.0 1.5 24.6 9.019.3 9.0 19.5 10 Average 35.5 ± 2.1 2.0 30.8 ± 10.0 5.7 23.1 ± 4.7 7.015.5 ± 6.5 6.5

The average relative bioavailability for the four dosage forms is shownin Table 3. The dose of the immediate release tablet was measured to be519 mg ciprofloxacin per tablet, instead of the labeled 500 mg. Withthis taken into account, the relative bioavailability of the GR-1 andGR-2 caplets was equivalent to that of the immediate release tablet.

TABLE 3 Summary of Bioavailability and t_(max) Results Subject IR TabletGR-1 GR-2 GR-3 Relative 39.70 ± 0.05% 39.29 ± 0.06% 37.40 ± 0.05% 21.30± 0.09% Bioavailability t_(max)  2.0 ± 0.9 hrs  5.7 ± 3.1 his  7.0 ± 3.5his  6.5 ± 3.5 hrs

FIGS. 3 and 4 show the difference in absorption from the four dosageforms in the three subjects. As may be seen, the GR dosage forms didexhibit extended release profiles, and the AUC's were generallycomparable to the IR tablet.

Example 2

The results of the above in vivo study indicated that the releaseprofile of the GR dosage form should be optimized to take advantage ofthe average gastric residence time. The individual results from thethree subjects showed a high degree of variability, due in part to thevariability in the rate of drug release from the tablet (i.e., thedifference between the disintegration and dissolution release profiles).In order to minimize patient-to-patient variability, formulations weremodified so that the in vitro release profile obtained using adisintegration test would approximate the dissolution release profile.

The evaluation procedures were the same as those described above, andthe formulations together with the symbols used in FIG. 5 where theresults are plotted, were as follows:

Squares, solid line: Dissolution test results for 81.62 wt. %ciprofloxacin HCl,

-   -   13.86 wt. % Polyox® WSR N-60K, 2.52 wt. % PVP, 2.0 wt. %        magnesium stearate.    -   Tablet dimensions of 10.03×5.94×16.09 mm, tablet weight of 666        mg (containing 544 mg ciprofloxacin HCl), N=6.

Squares, dashed line: Disintegration test results for 81.62 wt. %ciprofloxacin HCl,

-   -   13.86 wt. % Polyox® WSR N-60K, 2.52 wt. % PVP, 2.0 wt. %        magnesium stearate.    -   Tablet dimensions of 10.03×5.94×16.09 mm, tablet weight of 666        mg (containing 544 mg ciprofloxacin HCl), N=6.

Triangle, solid line: Dissolution test results for 69.38 wt. %ciprofloxacin HCl,

-   -   11.78 wt. % Polyox® WSR N-60K, 15% microcrystalline cellulose        (MCC), 2.14 wt. % PVP, 1.7 wt. % magnesium stearate.    -   Tablet dimensions of 0.03×5.76×16.06 mm, tablet weight of 800 mg        (containing 555 mg ciprofloxacin HCl), N=6.

Triangle, dashed line: Disintegration test results for 69.38 wt. %ciprofloxacin HCl,

-   -   11.78 wt. % Polyox® WSR N-60K, 15% microcrystalline cellulose        (MCC), 2.14 wt. % PVP, 1.7 wt. % magnesium stearate.    -   Tablet dimensions of 10.03×5.76×6.06 mm, tablet weight of 800 mg        (containing 555 mg ciprofloxacin HCl), N=6.

Circles solid line: Dissolution test results for 61.35 wt. %ciprofloxacin HCl,

-   -   14.78 wt. % Polyox® WSR N-60K, 21.87 wt. % Polyox® WSR N-80, 2.0        wt. % stearic acid.    -   Tablet dimensions of 8.75×6.45×19.01 mm, tablet weight of 901 mg        (containing 553 mg ciprofloxacin HCl), N=3.

Circles, dashed line: Disintegration test results for 61.35 wt. %ciprofloxacin

-   -   HCl, 14.78 wt. % Polyox® WSR N-60K, 21.87 wt. % Polyox® WSR        N-80, 2.0 wt. % stearic acid.    -   Tablet dimensions of 8.75×6.45×19.01 mm, tablet weight of 901 mg        (containing 553 mg ciprofloxacin HCl), N=3.

X's, solid line: Dissolution test results for 60.82 wt. % ciprofloxacinHCl,

-   -   9 wt. % Polyox® 301, 25.65 wt. % Polyox® WSR N-80, 2.53 wt. %        PVP, 2.0 wt. % magnesium stearate.    -   Tablet dimensions of 12.04×6.24×19.06 mm, tablet weight of 909        mg (containing 553 mg ciprofloxacin HCl), N=3.

X's, dashed line: Disintegration test results for 60.82 wt. %ciprofloxacin HCl,

-   -   9 wt. % Polyox® 301, 25.65 wt. % Polyox® WSR N-80, 2.53 wt. %        PVP, 2.0 wt. % magnesium stearate.    -   Tablet dimensions of 12.04×6.24×19.06 mm, tablet weight of 909        mg (containing 553 mg ciprofloxacin HCl). N=3.

The formulation containing 13.86% Polyox® N-60K showed a 3-4 hourdisintegration profile and approximately 9-hour dissolution profile.When the tablet size was increased to 900-mg and the ratio of drug toPolyox® N-60K was kept constant (using MCC as filler), the increase intablet size resulted in a slower release rate, both for disintegration(approximately 5 hours) and dissolution (76% at 8 hours). Theformulation containing 9% Polyox® 301/25.65% Polyox® N-80 showed afaster disintegration release of 2-3 hours and a dissolution releaseprofile of approximately 8 hours. The presence of Polyox® N-80 appearedto act as an effective tablet disintegrant, while the Polyox® 301provided tablet integrity. Also, while the Polyox® 301 prevented thetablet from disintegrating too quickly, the Polyox® N-80 allowed for adiffusional release from the tablet matrix.

FIG. 6 summarizes the data obtained with bi-layer and tri-layerciprofloxacin HCl tablets. The bi-layer tablets contained an activelayer and a 300-mg swelling layer (Polyox® 303). The tri-layer tabletscontained active layers on the top and bottom with a 300-mg Polyox® 303layer in the middle. The evaluation procedures were the same as thosedescribed above, and the formulations together with the symbols used inFIG. 6 where the results are plotted, were as follows:

Circles, solid line: Dissolution test results for bilayer tablet, withlayer 1 containing

-   -   60.67 wt. % ciprofloxacin HCl, 34.8 wt. % Polyox® WSR N-80, 2.53        wt. % PVP, 2.0 wt. % magnesium stearate, and layer 2 containing        300 mg Polyox® 303.    -   Tablet weight of 1213 mg (containing 554 mg ciprofloxacin HCl),        tablet dimensions of 12.02×7.85×19.03 mm, N=3.

Circles, dashed line: Disintegration test results for bilayer tablet,with layer 1 containing

-   -   60.67 wt. % ciprofloxacin HCl, 34.8 wt. % Polyox® WSR N-80, 2.53        wt. % PVP, 2.0 wt. % magnesium stearate, and layer 2 containing        300 mg Polyox® 303.    -   Tablet weight of 1213 mg (containing 554 mg ciprofloxacin HCl),        tablet dimensions of 12.02×7.85×19.03 mm, N=3.

Triangle, solid line: Dissolution test results for bilayer tablet, withlayer 1 containing

-   -   60.67 wt. % ciprofloxacin HCl, 25 wt. % Polyox® WSR N-80, 9.8        wt. %    -   Avicel® PH-101 (MCC), 2.53 wt. % PVP, 2.0 wt. % magnesium        stearate, and layer 2 containing    -   300 mg Polyox® 303.    -   Tablet weight of 1217 mg (containing 556 mg ciprofloxacin HCl),        tablet dimensions of 12.03×7.79×19.05 mm, N=3.

Triangle, dashed line: Disintegration test results for bilayer tablet,with layer 1 containing

-   -   60.67 wt. % ciprofloxacin HCl, 25 wt. % Polyox® WSR N-80, 9.8        wt. %    -   Avicel® PH-101 (MCC), 2.53 wt. % PVP, 2.0 wt. % magnesium        stearate, and layer 2 containing    -   300 mg Polyox® 303.    -   Tablet weight of 1217 mg (containing 556 mg ciprofloxacin HCl),        tablet dimensions of 12.03×7.79×19.05 mm, N=3.

X's, solid line: Dissolution test results for trilayer tablet, withouter layers each containing

-   -   46.08 wt. % ciprofloxacin HCl, 10 wt. % Polyox® 301, 40 wt. %        Polyox®    -   WSR N-80, 1.92 wt. % PVP, and 2.0 wt. % magnesium stearate, and        middle layer containing    -   300 mg Polyox® 303.    -   Tablet dimensions of 12.00×6.36×19.03 mm, tablet weight of 901        mg (554 mg ciprofloxacin HCl), N=3.

X's, dashed line: Disintegration test results for trilayer tablet, withouter layers each containing

-   -   46.08 wt. % ciprofloxacin MCl, 10 wt. % Polyox® 301, 40 wt. %        Polyox®    -   WSR N-80, 1.92 wt. % PVP, and 2.0 wt. % magnesium stearate, and        middle layer containing    -   300 mg Polyox® 303.    -   Tablet dimensions of 12.00×6.36×19.03 mm, tablet weight of 901        mg (containing 554 mg ciprofloxacin HCl). N=3.

Example 3

Two formulations (500 mg) of gastric retentive tablets of ciprofloxacinhydrochloride were fabricated under GMP conditions at MDS PharmaServices (Tampa, Fla.). To ensure that ciprofloxacin would not bedelivered to the colon, the period of 90% drug release in USP Type Idissolution testing (0.1 N HCl, 100 rpm, pH=1) was designed to beapproximately 6 hours. Since retention and drug release represent abalance between swelling and erosion, respectively, 2 formulations wereselected. One formulation involved conventional tableting (GR-A) and theother swelled to a greater extent to ensure retention, but was moredifficult to manufacture (GR-B). Immediate release tablets (500 mg,Cipro®, Bayer) were used as obtained. The compositions of GR-A and GR-Bare given below.

GR-A: 74.26 wt. % ciprofloxacin HCl, 20 wt. % Polyox® 1105, 4.74 wt. %PVP,

-   -   1.0 wt. % magnesium stearate. Tablet dimensions of 10.1×6.5×18.1        mm, tablet weight of 796 mg (containing 508 mg ciprofloxacin).

GR-B: Layer 1: 59.41 wt. % ciprofloxacin HCl, 35.8 wt. % Polyox®

-   -   WSR N-80, 3.79 wt. % PVP, 0.99 wt. % magnesium stearate.    -   Layer 2: 300 mg Polyox® 303.    -   Tablet dimensions of 12.05×7.9×19.05 mm, tablet weight of 1280        mg (containing 500 mg ciprofloxacin).

Immediate Release (IR) Formulation (caplet. 8.75×6.35×19.09 mm):

-   -   500 mg ciprofloxacin tablet (Cipro®, obtained from Bayer        Corporation)

The dissolution and disintegration profiles obtained in vitro asdescribed in Example 1 are plotted in FIG. 7. The procedure was repeatedusing a bicarbonate buffered media (pH=6.8) instead of the 0.1 N HClsolution, and the results are plotted in FIG. 8. The procedure wassubstantially repeated using mammalian simulated intestinal fluid (mSIF)instead of the 0.1 N HCl solution, and Table 4 shows the percent ofciprofloxacin release from the GR-A formulation at 1 and 6 hours. TheGR-A formulation represented a 6-hour system with over 90% drug releasein 0.1 N HCl.

TABLE 4 Dissolution of Ciprofloxacin GR-A Tablets Percent Released (%)Receptor Media 1 hour 6 hour 0.1N HCl 15.2 91.6 mSIF 0.9 3.1 BicarbonateBuffer 0.5 3.4

An analytical test was performed on the solubility of ciprofloxacin inthree different solutions, deionized water (DI), mSIF, and abicarbonate-buffered solution. Ciprofloxacin was added to each solventgradually until the solution became saturated. Each mixture was thencentrifuged and the concentration of ciprofloxacin in the supernatantwas analyzed by high performance liquid chromatography. The results areprovided in Table 5.

TABLE 5 Solubility of Ciprofloxacin Hydrochloride Solubility of pHBefore adding pH After Adding iprofloxacin Ciprofloxacin CiprofloxacinHCl Receptor Media HCl HCl (mg/mL) 0.1N MCI 5.8 3.8 30 mSIF 6.8 6.7 0.1Bicarbonate Buffer 6.8 8.2 0.1

Ciprofloxacin was found to be very insoluble in both mSIF andbicarbonate-buffered solution (pH=6.8).

Example 4

The pharmacokinetics of two formulations of gastric retentive tablets ofciprofloxacin hydrochloride and the immediate release tablet (Cipro® 500mg base) were compared in 15 healthy volunteers. Retention in thestomach in the fed mode was based on polymeric swelling, and drugrelease was based on polymeric erosion. Extended release profiles wereobserved for the gastric retentive tablets with comparablebioavailability to the immediate release tablet.

A single dose, 3-way, open-label, randomized crossover study wasconducted under GCP in 15 healthy volunteers at the AAI facility inNeu-Ulm, Germany. All treatments were administered within 5 minutesafter a 500-calorie, moderate fat breakfast. There was a 5-day wash outperiod between treatments. All volunteers were screened and signedinformed consent forms prior to enrolling in the study. Plasma sampleswere taken at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 5, 10, 12, 14, 16, 20, and 24hours after dosing. Urine was collected for 36 hours. Ciprofloxacin wasanalyzed in plasma and urine by HPLC. Noncompartmental parameters werecalculated for the plasma data. Statistical differences were detected byANOVA (p<0.05).

The mean±S.D. for the pharmacokinetic parameters for each treatment isreported in Table 6. There were no statistical differences in AUC amongtreatments. The mean bioavailabilities of the two gastric retentivetablets were approximately 90% relative to the immediate release tablet.Statistical differences were detected in terms of a reduction of C_(max)and a greater t_(max) for the gastric retentive tablets compared to theimmediate release tablet. No statistical differences were observedbetween the 2 gastric retentive tablets. Both gastric retentive tabletsyielded extended release plasma profiles without significant loss ofbioavailability. Plasma profiles in terms of plasma levels versus timeare plotted in FIG. 9. In this study, there was a trend toward lessvariability with the GR-B tablet, but this difference is well withinexperimental variation. The intersubject variation in delivery for bothgastric retentive tablets was comparable to the variation for theimmediate release tablet.

TABLE 6 Noncompartmental PK Parameters for Treatments AUC Relative CmaxTmax Treatment (ng-h/ml) Bioavailability (ng/ml) (h) IR 7320 ± 2030 —1780 ± 580 1.2 ± 0.7 GR-A 6420 ± 2340 0.88 ± 0.21 1090 ± 410*** 3.6 ±2.0*** GR-B 6790 ± 2350 0.92 ± 0.17 1030 ± 390*** 3.7 ± 1.5*** ***p <0.001

All three treatments were well tolerated and the adverse reactions weremild and did not appear drug related. Both gastric retentive tabletsprovided extended duration of plasma profiles for ciprofloxacin and hadcomparable bioavailability to the immediate release tablet.

1. A dosage form comprising: a polymer matrix and a neuroleptic agentdispersed in said polymer matrix, said polymer matrix comprised of apolymer wherein the polymer matrix: (a) upon imbibition of water swellsto a size effective to promote gastric retention for a time period ofabout 2 to 12 hours, and (b) maintains the size for the time periodbefore the polymer matrix is diminished by erosion, wherein at least 75wt % of the neuroleptic agent is released by erosion of the polymermatrix within the time period.
 2. The dosage form of claim 1, whereinthe dosage form is a bilayer or trilayer tablet.
 3. The dosage form ofclaim 1, wherein the neuroleptic agent is selected from the groupconsisting of an antidepressant, an antimanic and an antipsychotic drug.4. The dosage form of claim 1, wherein the neuroleptic agent isquetiapine or a pharmaceutically acceptable salt thereof.
 5. The dosageform of claim 1, wherein at least 40 wt % of the neuroleptic agent isreleased within 4 hours.
 6. The dosage form of claim 1, wherein at least80 wt % of the neuroleptic agent is released within the time period. 7.The dosage form of claim 1, wherein the dosage form comprises atherapeutically effective amount of the neuroleptic agent.
 8. The dosageform of claim 1, wherein the neuroleptic agent in the dosage form ispresent in a range of about 0.01% to 80% of the dosage form by volume.9. The dosage form of claim 1, characterized by an erosion rate (ER) todissolution rate (DR) ratio of approximately 1.1:1 to 5:1, wherein ER isthe rate of the neuroleptic agent release in an aqueous medium measuredusing an in vitro disintegration test, and DR is the rate of theneuroleptic agent release in an aqueous medium measured using an invitro dissolution test.
 10. The dosage form of claim 1, wherein thedosage form characterized by an ER to DR ratio of approximately 1.2:1 toapproximately 3:1.
 11. The dosage form of claim 1, wherein the dosageform is characterized by an ER to DR ratio of approximately 1.3:1 toapproximately 2:1.
 12. The dosage form of claim 1, wherein the dosageform is characterized by an ER to DR ratio of approximately 1.5:1 toapproximately 2:1.
 13. The dosage form of claim 1, wherein the dosageform comprises a second active agent.
 14. A dosage form comprising: apolymer matrix and quetiapine or pharmaceutically acceptable saltthereof dispersed in the polymer matrix, the polymer matrix comprised ofa hydrophilic polymer, wherein the polymer matrix: (a) upon imbibitionof water swells unrestrained dimensionally to a size effective topromote gastric retention for a time period of about 2 to 12 hours, and(b) maintains the size for the time period before the size is diminishedby erosion, wherein at least 75 wt % of the quetiapine in the dosageform is released by erosion of the polymer matrix within the timeperiod.
 15. The dosage form of claim 14, wherein greater than 90 wt % or95 wt % of the quetiapine is released within about 8 hours.
 16. Thedosage form of claim 14, wherein greater than 90 wt % or 95 wt % of thequetiapine is released within about 6 hours.
 17. A dosage formcomprising: a first layer comprising a polymer matrix and a second layercomprising a neuroleptic agent or pharmaceutically acceptable saltthereof, wherein the first layer: (a) upon imbibition of water swells toa size effective to promote gastric retention of the dosage form for atime period of about 2 to 12 hours, and (b) maintains the size for thetime period before the size is diminished by erosion. wherein at least75 wt % of the neuroleptic agent in the dosage form is released from thedosage form within the time period.
 18. The dosage form of claim 17,wherein greater than 90 wt % or 95 wt % of the neuroleptic agent isreleased within about 8 hours.